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Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

Sepideh Mirzaei, Kiavash Hushmandi, Amirhossein Zabolian and 9 more

Molecules · 2021 · Review · CC BY

doi:10.3390/molecules26082382

Abstract

The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The field of cancer chemotherapy is suffering from a number of challenges; drug resistance is the most significant. In respect to the benefits of chemotherapy in the treatment of cancer patients, factors responsible for mediating chemoresistance should be identified in further studies, in order to prevent drug resistance. Cisplatin (CP) is a platinum-containing drug that was first discovered in 1965 and became famous due to its great antimicrobial activity. More experiments demonstrated that platinum-containing agents can possess anti-cancer activity. As an electrophilic reagent, platinum can interact with nucleophilic residues of nucleobases, including guanine and adenosine by forming covalent bonds. Due to the presence of nucleophilic residues on a wide variety of cellular components, platinum-containing compounds can interact with ribosomes, spliceosomes, RNA and proteins. The major pathway for suppressing cancer progression by CP is inducing DNA damage by forming adducts with DNA, resulting in apoptosis and cell cycle arrest. More efforts in revealing anti-tumor activity of CP revealed that CP has the capacity of internalization in organelles, such as endoplasmic reticulum (ER), mitochondrion, lysosomes, and nucleus. This demonstrates that, in addition to DNA damage, CP can induce cell death by impairing homeostasis of vital organelles, such as ER and mitochondrion. However, this impact may negatively affect anti-tumor activity of CP. It has been reported that in spite of impairing homeostasis of proteins and organelles in cytoplasm upon CP accumulation, pro-survival mechanisms, such as autophagy, unfolded protein response (UPR) and other protective processes may be activated. These mechanisms may induce cancer cells resistance to CP chemotherapy.

Upon administration, CP immediately emerges in blood circulation. A high amount of CP (up to 98%) can be found in status of connected to plasma proteins, such as human serum albumin (HAS). Each HAS can bind to five CP molecules. One of the problems in patients receiving CP is the emergence of zinc imbalance. This is due to binding capacity of HAS-CP to histidine residues that are involved in transportation of Zn2+ ions in cells. The penetration of CP into cells is performed via passive diffusion.

The benefits of using CP in cancer chemotherapy became absent as a result of chemoresistance. Cancer cells no longer become responsive to CP chemotherapy and can upregulate molecular pathways to induce drug resistance. A wide variety of factors are considered as key players in mediating CP resistance. Drug transporters participate in triggering CP resistance. ATP7A and ATP7B are copper transporters that can bind to cysteine residue of CP to diminish its internalization in cells, leading to chemoresistance. It has been reported that enhanced activity and expression of P-glycoprotein (P-gp) can also stimulate CP resistance. On the other hand, in CP-resistant cancer cells, pro-apoptotic factors, such as BCL2 associated X (BAX) undergo down-regulation, while an increase occurs in the expression of anti-apoptotic factors, such as Bcl-2 to trigger CP resistance. It seems that glutathione peroxidase 4 (GPX4) upregulation prevents ferroptosis in cancer cells to mediate CP resistance. In this case, the inhibition of these antioxidant agents can predispose cancer cells to CP chemotherapy. In head and neck cancer cells, down-regulating glutaredoxin 5 stimulates ferroptosis, leading to CP sensitivity. Transcriptional activation of RAD51 by CtBP1 results in CP resistance. Noteworthy, it appears that CP administration can significantly promote metastasis and invasion of cancer cells by inducing macrophages. The experiments have also tried to target molecular pathways involved in CP resistance via anti-tumor agents. For instance, propofol and hederagenin are among anti-tumor agents that can promote CP sensitivity of cancer cells by down-regulating Wnt signaling and suppressing autophagy.

As mentioned earlier, the impact of CP on intracellular organelles might pave the way for CP resistance. In the present review, our aim is to reveal the role of reactive oxygen species (ROS) in mediating/suppressing CP resistance. This review focuses on molecular pathways to relate ROS generation with efficacy of CP chemotherapy in cancer therapy. Future experiments can focus on targeting molecular pathways involved in this review articles and we have provided some examples in this case.

2.1. Basics

Reactive species have gained much attention in the field of biology and medicine, and to date, different kinds of reactive species have been recognized, based on their source, being either oxygen, nitrogen or sulfur. ROS are derived from oxygen through some reactions such as reduction-oxidation reactions or electronic excitation. There are four major types of ROS, including superoxide, hydrogen peroxide, peroxyl radical and lipid peroxidase. As chemically active free radicals, ROS play a remarkable role in tissue homeostasis. The production of ROS occurs in mitochondrion and this is performed during mitochondrial respiration and inducing the partial reduction of oxygen. In addition to mitochondria, other cellular organelles, such as ER and peroxisomes can participate in ROS formation. It has been reported that ROS can interact with proteins, lipids and genetic materials in cells. The imbalance in the generation of ROS can lead to the emergence of oxidative stress with the dual role of being beneficial or harmful. The physiological functions of cells, such as aging, inflammation and immune responses are governed by ROS. Therefore, the presence of ROS is vital for normal function of cells. However, increased levels of ROS production can result in the development of pathological events, including neurodegenerative diseases, diabetes and cancer.

ROS participate in redox signaling and in this case, their low level generated by mitochondrial respiration or nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase (NOX) is required. In redox signaling, ROS regulate a variety of molecules, including protein kinases and transcription factors to monitor proliferation, differentiation, migration and cytokine production. The opposite term of redox signaling is redox modulation that ROS action does not rely on first messenger (extracellular stimuli) and ROS induce changes in characteristics of redox-sensitive molecules, such as nucleic acid and metabolic enzymes. One of the most well-known pathways that ROS participate is apoptosis induction. Enhanced generation of ROS disrupts mitochondrial homeostasis, and this leads to the upregulation of apoptotic factors, such as Bax and Bid, and down-regulation of anti-apoptotic factors, such as Bcl-2. Then, the release of cytochrome C (cyt C) from mitochondrion occur, leading to activation of caspase cascade and apoptotic cell death. Furthermore, ROS can impair ER homeostasis to stimulate apoptosis.

2.2. ROS Role in Cancer

In the previous section, we have summarized the role of ROS production, their role in physiological conditions and related pathways. In this section, an overview of the ROS role in cancer progression/inhibition is provided to shed some light on its targeting pathways in cancer therapy. The molecular pathways that are regulated by ROS are of importance in cancer therapy. Increased ROS generation leads to the activation of p38 and extracellular signal-regulated kinase (ERK), which subsequently stimulates cell death and cell cycle arrest at S and G2/M phases. Organelles are vital targets of ROS in cancer cells. Upon ROS overgeneration, ER stress occurs, and related molecular pathways, including glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) undergo upregulation that trigger anti-tumor activity. Previously, it was mentioned that an increase in ROS generation impairs mitochondrial homeostasis. It has been reported that by triggering mitochondrial damage, ROS promotes the expression level of FOXO3a in mediating its nuclear translocation. In the nucleus, FOXO3a enhances expression level of tumor-suppressing factors, such as Bim caspase-3 and phosphatase and tensin homolog (PTEN) to induce apoptosis in cancer cells. This study clearly demonstrates that by regulating mitochondria, ROS can induce apoptosis. In addition to apoptotic cell death, ROS overgeneration can stimulate ferroptosis in decreasing proliferation and viability of cancer cells. Autophagy is another programmed cell death (PCD) mechanism that can be stimulated by ROS levels in cancer therapy. In lung cancer cells, increased ROS generation leads to stimulation of mitogen-activated protein kinase (MAPK) that in turn, induces ERK and c-Jun N-terminal kinase (JNK) pathways. Then, autophagic cell death occurs that remarkably diminishes proliferation and growth of lung cancer cells. Therefore, elevating ROS generation is the most important pathway that anti-tumor agents follow in cancer elimination. One of the forms of autophagy is mitophagy that degrades damaged mitochondrion. ROS overgeneration leads to mitochondrial injury and provides the conditions for mitophagy, resulting in a decrease in cancer cell viability. Noteably, in respect to the role of ROS in reducing cancer cell viability, it has been reported that cancer stem cells (CSCs) preserve ROS generation at low levels to obtain chemoresistance. Therefore, using agents that enhance ROS generation is improtant in providing chemosensitivity. Overall, studies are in agreement with anti-tumor activity of ROS and their capacity in regulating various molecular pathways. However, there are controversies about the role of ROS in cancer cells. Although previous statements demonstrate the role of ROS as anti-tumor agents, there are experiments showing the tumorigenesis role of ROS. Immune system plays a significant role in cancer therapy. In impairing anti-tumor activity of immune system, cancer-associated fibroblasts (CAFs) enhance ROS generation to provide polarization of monocytes to myeloid-derived suppressor cell (MDSC). It appears that hepatitis B virus (HBV) can enhance ROS generation in hepatocellular carcinoma. Enhanced ROS production leads to IQGAP1 and Rac1 interaction that overexpressed Rac1 induces Src/FAK signaling via phosphorylation to promote migration and invasion of cancer cells, and stimulate anoikis resistance. These studies demonstrate the dual role of ROS in cancer. In the next sections, a mechanistic discussion of ROS role in CP sensitivity/resistance is provided.

Cisplatin Sensitivity

The Krüppel-like factor 4 (KLF4) is a zinc finger-containing transcription factor capable of regulating different biological activities such as differentiation and tumorigenesis. The interaction partner and cell type determine role of KLF4 as a tumor-suppressing or tumor-promoting factor. The overexpression of KLF4 is in favor of enhancing CP-mediated apoptosis in cancer cells. In CP resistant-cancer cells, KLF4 and ROS undergo down-regulation that are responsible for increased cell viability. As their levels decrease simultaneously, KLF4 upregulation may promote ROS levels in enhancing CP sensitivity of cancer cells.

MicroRNAs (miRNAs) are regulators of different biological processes in cells, such as proliferation, migration, differentiation, apoptosis and autophagy. In addition to physiological roles, miRNAs also play a significant role in pathological events via regulating various molecular pathways. MiRNA-124 is a new emerging miRNA in cancer chemotherapy that its upregulation down-regulates oncogenic signal transducer and activator of transcription 3 (STAT3) pathway to promote CP sensitivity. Furthermore, it can be considered as a biomarker for determining response to CP chemotherapy, so that gastric cancer patients with low levels of miRNA-124 have poor response to CP chemotherapy. Noteworthy, miRNA-124 can regulate ROS levels in affecting CP response of cancer cells. In this way, miRNA-124 decreases SIRT1 expression to increase ROS levels that subsequently, stimulate JNK phosphorylation, leading to increased CP sensitivity of hepatocellular carcinoma cells. The same phenomenon occurs by miRNA-519d in colorectal cancer cells. MiRNA-519d is a critical regulator of cancer response to CP chemotherapy. MiRNA-519d can reduce expression level of XIAP to potentiate CP cytotoxicity against cancer cells. Furthermore, miRNA-519d impedes CP resistance by inducing apoptosis through MCL-1-dependent mitochondrial pathway. In colorectal cancer cells, miRNA-519d down-regulates the expression level of tripartite motif 32 (TRIM32) to enhance ROS levels, leading to mitochondrial dysfunction and increased CP sensitivity. Investigating the expression level demonstrates that miRNAs with tumor-suppressing role undergo down-regulation in CP resistant-cancer cells. Such phenomenon is obvious in cervical cancer in which miRNA-497 shows low expression, while an increase occurs in expression profile of transketolase (TKT) (upregulation in 81.1% of samples). By reducing TKT expression, miRNA-497 promotes ROS levels, while induces GSH depletion, leading to cancer cell death and CP sensitivity.

Recent experiments have focused on revealing role of sirtuin-2 (SIRT2) in cancer and providing rationale for its therapeutic targeting. SIRT2 can suppress migration and invasion of cancer cells via isocitrate dehydrogenase 1 (IDH1) deacetylation. Furthermore, SIRT2 can inhibit proliferation and colony-formation capacity of cancer cells. In ovarian cancer cells, enhancing SIRT2 expression paves the way for CP sensitivity. CP administration significantly increases ROS levels to induce SIRT2 expression, resulting in ovarian cancer suppression.

One of the targets in cancer therapy is ER, so that inducing ER stress enhances efficacy of chemotherapy in cancer eradication. Triggering ER stress and activating UPR are followed by CP in cancer treatment. In ovarian cancer cells, CP enhances ROS levels to induce ER stress. Then, UPR activates that overcomes drug resistance. It seems that ROS levels can be considered as a biomarker for predicting response of cancer cells to chemotherapy. For this purpose, Sun and colleagues have developed a scoring system, based on ROS, for predicting cancer patients’ response to CP chemotherapy. In this system, there are 25 scores in which scores 0–12 demonstrate low score groups, while scores 13–25 show high score groups. As ROS overgeneration enhances CP sensitivity and apoptosis induction, by enhancing ROS levels, patients are included in high score groups, which have high overall survival and good prognosis. This score can be used in clinical course. Furthermore, down-regulating molecular pathways modulating ROS can pave the way for CP sensitivity. The human paraoxonase (PON) family has three distinct members including PON1, PON2 and PON3. PON1 and PON3 are expressed in the liver, while PON2 demonstrates expression in various tissues and intracellular accumulation upon translation. It has been reported that PON2 possesses antioxidant activity in different tissues, such as the intestine and nervous system. The overexpression of PON2 is correlated with CP resistance. In order to increase CP sensitivity of melanoma cells, silencing PON2 promotes ROS levels, resulting in decreased viability and proliferation. Figure 1 and Table 1 demonstrate an overview of molecular pathways involved in CP sensitivity via ROS regulation.

4. Cisplatin Resistance

Inhibiting the expression of molecular pathways that reduce ROS levels and confer CP resistance is important in effective cancer chemotherapy. That is the reason why experiments have focused on the identification of such pathways and disrupting their expression. In head and neck cancers, ROS inhibition is associated with CP resistance. Enhancing ROS levels mediates ferroptosis and cell death. Nuclear factor erythroid 2-related factor 2 (Nrf2) is suggested to diminish ROS levels upon CP chemotherapy of head and neck cancer cells. Nrf2 signaling inhibition promotes ROS levels, potentiating ferroptosis and providing CP sensitivity.

It seems that ROS can provide metabolic reprograming to enhance resistance of non-small cell lung cancer (NSCLC) cells to CP. In this way, exposing NSCLC cells to CP is associated with an increase in mitochondrial function, PPAR-gamma coactivator-1α (PGC-1α) and mitochondrial. Simultaneously, glycolysis down-regulation occurs, but this does not affect cell cycle progression of cancer cells. These metabolic changes are mediated via ROS, so that ROS can promote PGC-1α expression and mitochondrial mass that are in favor of CP resistance. The inhibition of PGC-1α or suppressing oxidative phosphorylation enhance CP sensitivity of NSCLC cells. This experiment highlights the fact that we should consider metabolic reprogramming resulted from ROS and take strategies for overcoming this condition. The stimulation of factors involved in reducing ROS levels can promote CP resistance of NSCLC cells. Nrf2 participates in regulating redox balance and its activation is correlated with a decrease in ROS levels, and protecting cells against cell death. Furthermore, Nrf2 activation can diminish ROS levels and prevent ferroptosis in cancer cells. However, Nrf2 activation can diminish ROS levels in favor of inhibition of cell death in cancer cells and providing chemoresistance. Such association has been examined in triggering CP resistance. It has been reported that polarity protein Scribble enhances CP sensitivity of NSCLC cells. However, in vitro and in vivo experiments have shown down-regulation of this factor in CP resistant-NSCLC cells. Upon Scribble down-regulation, proteasomal degradation of NADPH oxidase 2 (Nox2) occurs that subsequently, ROS levels decrease. On the other hand, Nrf2 signaling activation results from Scribble down-regulation that can also participate in decreasing ROS levels. These impacts together lead to the development of CP resistance in NSCLC cells and a reduction in CP-mediated apoptosis. This experiment has potential application in clinical studies, since CP poses increasing challenges in the treatment of cancer patients, and if such signaling networks are affected in clinical course, we can prevent chemotherapy failure.

ROS inhibition can activate molecular pathways involved in cancer progression and phosphoinositide 3-kinase (PI3K)/protein kinase-B (Akt) is one of them. It has been reported that activation of PI3K/Akt axis not only promotes proliferation and metastasis of cancer cells, but also triggers chemoresistance. Therefore, it is important to reveal the role of this molecular pathway in CP resistance of cancer cells and providing prospects for its targeting. In CP-resistant NSCLC cells, glutathione peroxidase 1 (GPX1) remarkably diminishes ROS levels to stimulate Akt signaling, as a tumor-promoting factor for CP resistance. The investigation of molecular pathways demonstrates that master transcription factor nuclear factor-kappaB (NF-κB) functions as upstream mediator of GPX1 in CP resistance, so that NF-kB inhibition leads to CP sensitivity of NSCLC cells. GPX2 is also involved in CP resistance via reducing ROS levels, paving the way for failure of CP in lung cancer chemotherapy.

To be more specific about mechanisms involved in CP resistance, the significant role of drug transporters in this process should be considered and how they interact with ROS overgeneration. The enhanced activity of ATP-binding cassette (ABC) transporters such as multidrug resistance protein 1 (ABCB1) is suggested to induce CP resistance. Importantly, revealing molecular pathways, regulating ABCB1 expression and activity, is of importance for providing a platform for next targeting in cancer treatment and enhancing CP sensitivity. It has been reported that EF hand domain-containing protein 2 (EFHD2) as a calcium-binding protein enhances production of NOX4 to promote ROS generation. Subsequently, ROS generation function as upstream mediator of ABCB1 to enhance its expression, resulting in CP resistance.

In the tumor microenvironment of cancer cells, some changes can occur to ensure progression and proliferation. The pyruvate kinase isoenzyme type M2 (PKM2) is a regulator of Warburg impact in cancer cells and can enhance glycolysis in cancer cells via catalyzing synthesis of pyruvate from phosphoenolpyruvate (PEP). Increasing evidence demonstrate the therapeutic potential of targeting PKM2 in cancer and enhancing CP sensitivity. Exosomal transfer of PKM2 in hypoxic condition results in the generation of reductive metabolites that counter CP-mediated ROS production, preventing apoptosis and DNA damage and providing condition for CP resistance.

Thioredoxin (TRX1) is a disulfide-reducing dithiol enzyme and as an antioxidant enzyme plays a vital role in reduction of enzymes. Recently, attention has been directed towards the role of TRX1 in cancer, particularly drug resistance. It has been reported that TRX inhibition inhibits drug resistance and viability of cancer cells via suppressing Akt phosphorylation and promoting caspase-3 expression. Anti-tumor compounds, such as isodeoxyelephantopin are capable of down-regulating TRX1 and stimulating ROS-induced JNK signaling, leading to enhanced CP sensitivity. Down-regulating TRX1 is suggested to promote dependency of cancer cells on oxidative metabolism. Furthermore, TRX1 down-regulation enhances ROS generation in cancer cells to increase their CP sensitivity.

One of the important aspects is the regulation of CP sensitivity by miRNAs. Furthermore, miRNAs can modulate ROS levels in cells. Therefore, understanding the role of miRNAs in regulating ROS levels in CP chemotherapy is significant. MiRNA-140 is a tumor-suppressing factor that enhances CP sensitivity of cancer cells via down-regulating Wnt signaling. In increasing CP sensitivity, miRNA-140 down-regulates SIRT1 expression to promote ROS levels. Then, ROS induces JNK phosphorylation to increase CP-mediated apoptosis. As more experiments are performed, different molecular pathways are revealed that mediate CP resistance of thoracic cancers. The tumor necrosis factor receptor-associated protein 1 (TRAP1) is a new therapeutic target in cancer. This mitochondrial heat shock protein can be found in other locations of cells such as nucleus, cytoplasm and endoplasmic reticulum. It seems that upregulation of TRAP1 triggers drug resistance of cancer cells and prevents apoptosis. The CP resistant-lung cancer cells demonstrate high expression level of TRAP1 and apoptosis inhibition. Silencing TRAP1 is associated with increase in capacity of CP in cancer elimination by enhancing ROS levels and mediating mitochondrial dysfunction.

In the introduction section, it was mentioned that ROS can induce apoptosis via triggering mitochondrial dysfunction. Furthermore, it was described that enhanced ROS overgeneration can enhance tumorigenesis. Such an association between ROS and mitochondrial dysfunction in enhancing gastric cancer progression has been evaluated. The eukaryotic initiation factor 2α (eIF2α)-ATF4 axis is a regulator of stress response and can provide conditions in favor of cell survival upon stressful conditions and preventing apoptosis. There are different contributors of elF2a including dsRNA-activated protein kinase R (PKR), heme-regulated inhibitor eIF2α kinase (HRI), protein kinase R-like endoplasmic reticulum kinase (PERK), and general control nonderepressible-2 (GCN2) that are stimulated in various stress conditions. When mitochondrial dysfunction occurs, GCN2 or PERK can enhance elF2α expression. Exposing gastric cancer cells to CP increases expression level of SLC7A11 (×CT). It seems that mitochondrial dysfunction is responsible for enhanced ×CT and GSH expressions. Studies of the molecular pathways demonstrate that GCN2 can stimulate eIF2α/ATF4 axis to induce mitochondrial dysfunction, leading to enhanced ×CT and ROS levels, as well as triggering CP resistance. Another experiment also reveals role of ×CT in CP resistance. However, in this study, upstream mediator of salubrinal plays an important. Salubrinal enhances expression level of ×CT to increase GSH expression, and silencing ×CT is associated with inability of salubrinal in triggering CP resistance, showing that ×CT is vital for this process. Furthermore, as ×CT enhances GSH expression, they may involve in reducing ROS levels and triggering CP resistance.

Noteworthy, molecular pathways that protect cancer cells against oxidative stress damage, can lead to CP resistance. Peroxiredoxin 2 (PRDX2) is a supporter of cells against oxidative damage via reducing ROS and H2O2 levels. In gastric cancer cells, PRDX2 in cooperation with NF-kB-p65 subunit diminish ROS levels to suppress DNA damage and cell death, leading to CP resistance. It seems that ROS participate in mechanisms that suppress CP-mediated apoptosis and mediate chemoresistance.

Recent years, much emphasis has been directed towards role of tumor microenvironment in cancer progression. Low levels of angiogenesis and high proliferation of cancer cells induce hypoxic conditions in the tumor microenvironment that are accompanied by an increase in expression level of hypoxia inducible factor-1α (HIF-1α) providing the conditions for cancer growth. On the other hand, in response to different changes in the tumor microenvironment, alterations in structures and dynamics of mitochondria occur. The dynamin-related protein 1 (Drp1) is involved in mitochondrion dynamics and its phosphorylation level determines its activation or inhibition. For instance, Drp1 phosphorylation at serine 616 in results in its activation and mitochondrial fission, while phosphorylation at serine 637 prevents Drp1 activation and subsequent mitochondrial fission. A recent study has clearly shed some light on the associations between mitochondria, hypoxia and CP resistance. In hypoxic conditions, an increase occurs in levels of ROS in ovarian cancer cells that subsequently, down-regulate the expression level of Drp1 (serine 637), resulting in mitochondrial fission and CP resistance. Furthermore, Mitofusins 1 and 2 (Mfn1 and 2) involving in mitochondrion dynamics are suppressed by hypoxia-mediated ROS to induce mitochondrial fission and CP resistance.

It is worth mentioning that ROS can associate metabolism and metastasis of cancer cells. Then, this relationship can be extended to even affect result of immunotherapy. Therefore, it is of great importance to understand ROS interaction with mechanisms involved in cancer metastasis and its association immune factors. Such relationships have been investigated in CP chemotherapy. It has been reported that high levels of ROS change the metabolic profile of lung cancer cells. This metabolism alteration leads to the reliance of lung cancer cells to mitochondrial oxidative metabolism than glucose. More investigations demonstrate that this metabolic alteration significantly enhances migration and invasion of lung cancer cells via EMT induction. Besides, EMT participates in triggering programmed death ligand-1 (PD-L1) upregulation that provides immune evasion of cancer cells. This study clearly demonstrates that ROS, proliferation, metastasis and the response of cancer cells to chemotherapy and immunotherapy are in close relationship with each other, and ROS play the central and key role.

One of the pathways CP follow in cancer suppression is inducing DNA damage and preventing cancer progression. However, activation of signaling networks involved in DNA damage repair can provide CP resistance of cancer cells. Such phenomenon in ovarian cancer cells that can be targeted in next studies for triggering CP sensitivity. Dual oxidase 1 (DUOX1) is a carcinogenesis factor via increasing hydrogen peroxide levels. Besides, DUOX1 can enhance ROS level to inhibit cell differentiation. On the other hand, ataxia telangiectasia and Rad3-related protein (ATR) is a serine/threonine protein kinase modulating DNA damage. It has been reported that ATR can induce Checkpoint kinase 1 (Chk1) to trigger DNA damage repair. In ovarian cancer cells, DUOXA1 significantly elevates the production of ROS in stimulating ATR/Chk1 axis, leading to CP resistance. The in vitro and in vivo experiments have confirmed role of DUOXA1-mediated ROS overgeneration in CP resistance, and for overcoming poor prognosis in patients, targeting this pathway is of importance.

In previous sections, we discussed how Nrf2 signaling can participate in CP resistance. Another experiment also demonstrates role of Nrf2 signaling in CP resistance with an emphasis on upstream mediator of signaling. Increasing evidence shows tumor-promoting role of sirtuin-5 (SIRT5) in different cancers. There is a dual relationship between SIRT5 and Nrf2 signaling in CP chemotherapy, so that SIRT5 can regulate Nrf2 signaling in reducing nephrotoxicity of CP. In ovarian cancer cells, overexpression of SIRT5 is associated with CP resistance and prevents CP-mediated proliferation inhibition and DNA damage via reducing ROS levels. In this way, SIRT5 stimulates Nrf2 signaling and its downstream target heme oxygenase-1 (HO-1) to reduce ROS levels. In fact, SIRT5/Nrf2 axis results in a reduction in ROS levels, and silencing SIRT5 or Nrf2 provides the way for CP sensitivity via ROS overgeneration. Another experiment also confirms how Nrf2 regulation by an upstream mediator can lead to CP resistance. In ovarian cancer cells with high expression level of p62, cancer cells are resistance to anti-tumor activity of CP. The investigation of molecular pathways demonstrates that p62 induces Nrf2 signaling via Keap1 down-regulation, resulting in reinforcement of antioxidant defense system and protection of cancer cells against inhibitory impact of CP. It has been reported that ROS can function as upstream mediator of tumor-promoting factors in CP resistance. Previously, we described the role of PGC-1α in CP resistance. In ovarian cancer cells, mitochondrial dysfunction enhances ROS levels to stimulate PGC-1α expression, leading to CP resistance. As more experiments are performed, more signaling networks involved in CP resistance of ovarian cancer cells are revealed. Figure 2 and Table 2 provide a summary of ROS and related molecular pathways in CP resistance.

5. Therapeutic Targeting

In respect of the fact that molecular pathways involved in CP resistance and their regulatory impact on ROS levels and signaling have been identified, experiments have focused on using anti-tumor compounds, which are mostly phytochemicals. In the section, we provide a mechanistic discussion around using these compounds and their signaling targets. Plant derived-natural compounds have opened a new gate in cancer therapy due to their multitargeting capacity. Melatonin is a hormone of pineal gland that is synthesized in other organs with higher concentrations. Recent studies have shown different biological and therapeutic activities of melatonin that anti-tumor activity is among them. Noteworthy, melatonin can be considered as a potent chemosensitizer agent. In this way, melatonin can also enhance anti-tumor activity of CP. For instance, it has been reported that melatonin can activate caspase-3/7 cleavage and induce cell cycle arrest in potentiating cytotoxicity of CP against lung cancer cells. Importantly, ROS plays a key role in mediating anti-tumor activity of melatonin and its capacity in promoting CP sensitivity. By enhancing ROS levels, melatonin activates intrinsic pathway of apoptosis, resulting in enhanced CP sensitivity of cervical cancer cells. In addition to apoptosis, melatonin can affect other pathway of programmed cell death, known as autophagy. Generally, autophagy is a “self-digestion” mechanism and its induction is of importance in cancer therapy. Increasing evidence demonstrate the close relationship between autophagy and ROS, so that ROS overgeneration can stimulate autophagy. By enhancing ROS levels, melatonin simultaneously induces autophagy and apoptosis. A similar strategy is followed by withaferin-A in enhancing CP sensitivity of oral cancer cells via enhancing ROS levels and triggering both apoptosis and autophagy. However, one hint should be considered that autophagy may stimulate chemoresistance, and when investigating dual relationship between autophagy and ROS, this aspect of autophagy should be highlighted and considered.

Emodin is a plant derived-natural compound with high anti-tumor activity. This potent anti-tumor agent can suppress cancer metastasis via inhibiting epithelial-to-mesenchymal transition (EMT). The anti-tumor activity of emodin is dose-dependent and can affect different molecular pathways, such as miRNA-34a and vascular endothelial growth factor receptor (VEGFR). In enhancing CP sensitivity of endometrial cancer cells, emodin targets ROS levels. In this way, emodin diminishes ROS levels to induce apoptosis and suppress tumor growth (both in vitro and in vivo). Another experiment also confirms the role of emodin in increasing ROS levels, and potentiating the anti-tumor activity of CP against bladder cancer cells. In fact, several signaling networks are affected by anti-tumor compounds in triggering CP sensitivity that enhancing ROS levels is one of them.

Previously, it was shown that Nrf2 signaling activation is in favor of CP resistance via reducing ROS levels. Noteworthy, anti-tumor compounds targeting Nrf2 signaling and enhancing CP sensitivity have been discovered. Exposing head and neck cancer cells to wogonin, as a flavonoid compound, significantly reduces expression level of Nrf2, leading to CP sensitivity through increasing ROS accumulation. Another experiment also reveals the down-regulation of Nrf2 upon CP and a novel polyphenol, known as (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23), to enhance ROS accumulation, resulting in cell death and increased CP sensitivity. However, we still have a long way in regulating Nrf2 signaling, since this study has just examined the expression level of Nrf2. What about anti-tumor compounds targeting Keap1 or nuclear translocation of Nrf2? Future experiments will appropriately respond to this question.

Allicin is another naturally occurring compound with the capacity to suppress cancer proliferation, increase radio-sensitivity, and down-regulate NF-κB signaling. Allicin is extensively applied with other chemotherapeutic agents. For instance, allicin can promote chemosensitivity of cancer cells via apoptosis induction, enhancing miRNA-486-3p level and reducing cancer cell viability. A newly conducted experiment has obviously demonstrated the role of allicin in CP sensitivity of lung cancer cells. In this way, allicin increases ROS levels to induce both autophagy and apoptosis, and trigger cell cycle arrest (S/G2-M phase). By increasing ROS levels, a decrease occurs in intracellular level of GSH that is in favor of apoptosis induction via caspase-3 and -7 stimulation. Previously, it was discussed that Akt phosphorylation and activation can promote cancer progression and induce chemoresistance. Interestingly, ROS can function as an upstream mediator of Akt signaling. Piperlongumine as an anti-tumor agent, promotes ROS levels and accumulation in lung cancer cells to suppress Akt signaling, leading to CP sensitivity. Another aspect is related to impact of anti-tumor compounds on CP-mediated DNA damage, so that by increasing ROS levels, anti-tumor compounds enhance p53 phosphorylation to induce DNA damage and cell death. The importance is efficacy of this combination in enhancing anti-tumor activity of CP in vivo, so that the combination of CP and shikonin effectively suppresses tumor growth in colon cancer (HCT116 xenograft tumor). Therefore, the next step can be translating these findings to clinical application for enhancing the overall survival of cancer patients and preventing chemotherapy failure.

Clarithromycin (CAM) is a well-known antibiotic that was first applied in 2005. CAM can affect both apoptosis and autophagy by enhancing cytotoxicity of 5-fluorouracil as a chemotherapeutic agent against colorectal cancer cells. A similar phenomenon occurs during CP chemotherapy. In this way, CAM significantly enhances ROS levels to impair ovarian cancer growth in vitro and in vivo, leading to CP sensitivity. However, the story is not always so simple. The dual role of ROS as a pro-survival and pro-death mechanism was extensively discussed in the introduction section. AXL is a receptor tyrosine kinase with a role in cancer that has been suggested to be tumor-promoting. In increasing metastasis of breast cancer cells and providing their immune evasion, AXL and Mertk cooperate together. It has been reported that the overexpression of AXL can induce mitogen-activated protein kinase (MAPK) and triggering therapy resistance. In ovarian cancer cells, decreasing AXL expression is correlated with CP sensitivity by suppressing glycolysis. A combination of CP and pemetrexed can sufficiently stimulate cell death in mesothelioma cells via enhancing ROS levels. However, ROS signaling activates AXL, which diminishes cytotoxicity against cancer cells. In providing effective cancer chemotherapy, it is better co-administer a AXL blocker such as BGB324 with CP and pemetrexed. This study reminds us that although anti-tumor compounds enhance ROS production in providing CP sensitivity, it should be noted that ROS can activate downstream targets with tumor-promoting roles such as AXL.

It is worth mentioning that CP can promote ROS levels in mediating cell death in cancer cells. However, when an anti-tumor agent, such as vitamin D is co-administered with CP, its potential in enhancing ROS levels enhances. Furthermore, a combination of CP with other anti-tumor compounds provide conditions for suppressing molecular pathways that can enhance cancer progression. For instance, plumbagin and CP induce JNK signaling, while they inhibit Akt/mTOR signaling to enhance ROS levels, leading to apoptosis, autophagy and decreased viability of tongue squamous cell carcinoma cells. NF-κB signaling pathway is a molecular pathway where overexpression paves the way for chemoresistance of cancer cells. Triptolide promotes intracellular accumulation of ROS to inhibit NF-κB signaling and down-regulate Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP) as anti-apoptotic factors, increasing CP sensitivity of ovarian cancer cells. Reducing glycolysis (Warburg effect) and impairing mitochondrial function are induced by ascorbate in increasing CP sensitivity of osteosarcoma cells (Figure 3). Overall, the following points can be concluded about using anti-tumor compounds, which are mostly phytochemicals and have roles in enhancing CP sensitivity of cancer cells:Anti-tumor compounds significantly promote intracellular accumulation of ROS to mediate intrinsic pathway of apoptosis via mitochondrial dysfunction,Molecular pathways responsible for cancer progression and mediating CP resistance are suppressed by anti-tumor compounds upon increasing ROS levels,Most of the anti-tumor compounds applied with CP in cancer chemotherapy are plant derived-natural products, and one of their drawbacks is their poor bioavailability that can be overcome using nanoparticles. This aspect is discussed in next section (Table 3 and Table 4).

Anti-tumor compounds significantly promote intracellular accumulation of ROS to mediate intrinsic pathway of apoptosis via mitochondrial dysfunction,

Molecular pathways responsible for cancer progression and mediating CP resistance are suppressed by anti-tumor compounds upon increasing ROS levels,

Most of the anti-tumor compounds applied with CP in cancer chemotherapy are plant derived-natural products, and one of their drawbacks is their poor bioavailability that can be overcome using nanoparticles. This aspect is discussed in next section (Table 3 and Table 4).

6. Gene Therapy

In relation to the fact that molecular pathways, responsible for CP resistance, have been identified, genetic tools can be employed in providing CP sensitivity. This strategy can be specified by targeting molecular pathways that regulate ROS in CP chemotherapy. Although a few experiments have evaluated role of gene therapy in affecting ROS and CP sensitivity, this section provides a mechanistic discussion with future prospects to show how genetic tools can be utilized for affecting ROS and CP sensitivity.

Previously, it was mentioned that HIF-1α is activated in hypoxic conditions and can promote cancer progression. As there is a close relationship between HIF-1α and cancer metabolism, targeting this molecular pathway is of importance in CP sensitivity. Among genetic tools, small interfering RNA (siRNA) has shown high potential in promoting CP sensitivity via down-regulating tumor-promoting factors. In this case, HIF-1α down-regulation by siRNA leads to a change in cancer metabolism from aerobic glycolysis to mitochondrial oxidative phosphorylation. Then, ROS overgeneration occurs, resulting in apoptosis and increased CP sensitivity. This experiment obviously demonstrates impact of siRNA on ROS-related molecular pathways and their role in CP chemotherapy. Furthermore, in order to promote the potential of siRNA in gene silencing, its delivery by attenuated Salmonella has been performed. In addition to HIF-1α, Nrf2 signaling role in CP resistance has been discussed before. It seems that down-regulating Nrf2 expression by siRNA paves the way for CP sensitivity via inhibiting HO-1, subsequent increase in ROS generation and promoting CP-mediated cell death. Future experiments can focus on developing nanoparticles for siRNA delivery, affecting molecular pathways regulating ROS and promoting CP sensitivity. More experiments are needed to target factors regulating ROS levels in CP chemotherapy, paving the way for cancer elimination. Furthermore, other kinds of genetic tools, such as CRISPR/Cas9 system and short-hairpin RNA (shRNA) can be utilized in this case.

7. Nanotherapeutics

In the previous section, a mechanistic discussion of the role of molecular pathways regulating ROS levels in CP resistance/sensitivity was provided. Then, it was shown that anti-tumor compounds can affect ROS levels in mediating CP sensitivity. However, these therapies suffer from poor bioavailability and provide a platform for their targeted delivery is important in increasing their efficacy in triggering CP sensitivity. Furthermore, upstream mediators of ROS can be targeted by genetic tools, such as siRNA. However, siRNA should first circulate in blood and then move to the tumor site. It may be degraded by enzymes, while circulating in blood, and also, its efficacy increases by targeted delivery thereby promoting its intracellular accumulation. In this section, we demonstrate how nanocarriers can be helpful in regulating ROS levels and providing CP sensitivity.

Nanoscale delivery systems can significantly promote intracellular accumulation of drugs in cells via mediating endocytosis. Another benefit of using nanocarriers is providing simultaneous chemotherapy and phototherapy in cancer eradication. Such a strategy has been applied for CP delivery and preventing drug resistance. In this case, mesoporous silica nanoparticles (MSNs) have been developed for CP delivery. In order to provide phototherapy capacity of MSNs, their surface modification by chlorin e6 (Ce6) was performed. The nanocarriers demonstrated good properties such as particle size of 100 nm and zeta potential of 18.2 mV. These nanoparticles penetrate into cancer cells through endocytosis to promote intracellular accumulation of CP. Exposure to 660 nm light irradiation induces phototherapy effect and significantly promote ROS production in lung cancer cells, leading to enhanced efficacy of CP in cancer elimination. Another experiment also demonstrates the role of photodynamic therapy in increasing ROS levels, and sensitizing cancer cells to apoptosis that are of importance in promoting their CP sensitivity. Overall, irradiation and photo-excitation are vital for promoting ROS levels and activating pro-apoptotic factors, such as p38 MAPK to increase CP sensitivity of cancer cells. It is worth mentioning that nanoparticles can also mediate co-delivery of CP with other anti-tumor compounds. Metformin is a potent anti-tumor compound that suppresses mammalian target of rapamycin (mTOR) via AMP-activated protein kinase (AMPK) upregulation, leading to CP sensitivity of cancer cells. For enhancing the efficacy of metformin and CP in cancer chemotherapy, nanoplatforms have been developed. It is worth mentioning that metformin- and CP-loaded nanoparticles can affect ROS. In this way, exposing colorectal cancer cells to CP- and metformin-loaded nanocubosomes is associated with an increase in ROS levels, that subsequently, enhance NADPH oxidase, while decreasing lactate dehydrogenase (LDH), leading to caspase-3 cleavage and chemosensitivity.

Curcumin is also a plant derived-natural compound with diverse therapeutic effects that anti-tumor activity is among them. Curcumin is extensively applied with CP in suppressing progression of cancer cells and providing their chemosensitivity via targeting molecular pathways and mechanisms such as apoptosis, metastasis, KLF4 and SOX2. Loading CP and curcumin on liposomal nanocarriers increases their potential in enhancing ROS levels and suppressing hepatocellular carcinoma progression. Another experiment also reveals role of curcumin-loaded nanoparticles in increasing ROS levels in oral cancer cells and sensitizing them to CP-mediated cell death. In fact, the field of materials science can direct us towards using agents capable of promoting ROS levels and reversing CP resistance. Such a strategy has been utilized recently by Sun and colleagues. In this way, they synthesized nanogel by conjugating chitosan to diallyl disulfide, and then, its grafting with valproate. The interesting point is that valproate induces 18-fold increase in p53 expression, and simultaneously, diallyl disulfide triggers 8-fold increase in ROS levels, leading to CP sensitivity. Furthermore, in vivo experiment also confirmed role of this nanogel in reducing tumor growth inhibition and CP sensitivity. A newly conducted experiment demonstrates that tocotrienols-, caffeic acid- and CP-loaded nanoemulsions can enhance ROS production up to 16.9%, and 30.2% in lung and liver cancers, respectively, that are importance in mediating cell death and preventing cell cycle progression.

Notably, carbon nanomaterials, such as graphene possess carcinogenesis impact. Applying such carriers for CP delivery may exert reverse effect and promote drug resistance of cancer cells. It has been reported that CP-loaded multiwalled carbon nanotubes significantly diminish ROS levels and induce failure of CP in mediating apoptosis in breast cancer cells, leading to development of drug resistance. Therefore, this aspect should be considered while synthesizing nanocarriers for CP delivery and suppressing cancer progression.

Overall, studies are in line with the fact that using nanoparticles is of importance in increasing ROS levels and sensitizing cancer cells to CP chemotherapy. Furthermore, nanocarriers can undergo surface modification to enhance their selectivity towards cancer cells. Finally, nanoparticles can provide phototherapy in promoting ROS generation, resulting in an increase in efficacy of CP in cancer chemotherapy (Figure 4).

8. Conclusions and Remarks

In the present review, a comprehensive discussion of ROS role in CP resistance/sensitivity was provided. Due to frequent application of CP, cancer cells have obtained resistance to this chemotherapeutic agent, and if an effective cancer chemotherapy is performed, molecular pathways and mechanisms responsible for CP resistance should be identified so they can be targeted through novel therapeutics. The exact role of ROS in cancer cells has not been completely determined, and it may act as a pro-survival or pro-death mechanism. This context-dependent role of ROS has resulted in much attention in revealing its role in CP resistance/sensitivity. Upstream mediators of ROS can affect response of cancer cells to CP chemotherapy, and noteworthy, downstream targets also play a significant role, as shown in this review. The important hint is that experiments have used therapeutic agents in targeting ROS and providing CP sensitivity. In this case, both genetic and pharmacological interventions have been performed. Anti-tumor compounds that are mostly phytochemicals, enhance ROS levels to mediate mitochondrial dysfunction and cell death. It should be noted that ROS can activate both autophagy and apoptosis. In contrast to apoptosis, autophagy can promote the progression of cancer cells. Therefore, if autophagy activation occurs following pharmacological intervention and enhancing ROS levels in CP chemotherapy, the exact role of autophagy should be determined, and if autophagy functions as a pro-survival mechanism, autophagy inhibitors, such as chloroquine can be utilized.

Another important aspect is using gene therapy to influence levels and CP chemotherapy. Similar to pharmacological intervention, genetic tools can also promote CP sensitivity via regulating ROS levels. However, the drawbacks of these strategies should also be considered. For instance, anti-tumor compounds suffer from poor bioavailability. Genetic tools, such as siRNA may undergo degradation while circulating in blood and it has an off-targeting feature. To overcome the aforementioned disadvantages, scientists have focused on developing nanoarchitectures. These nanocarriers provide targeted delivery, co-delivery with other anti-tumor agents and genetic tools, increased intracellular accumulation in cancer cells and promote ROS generation that are important in CP sensitivity. Although pre-clinical studies have investigated ROS and CP chemotherapy, future experiments can focus on developing novel therapies for targeting ROS in the treatment of cancer patients. Furthermore, if nanoparticle application is applied in this field, a biocompatibility profile should be considered.

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    Not in our library10.3390/ijms21218135

  67. 67.

    Nasimian A., Farzaneh P., Tamanoi F., Bathaie S.Z. Cytosolic and mitochondrial ROS production resulted in apoptosis induction in breast cancer cells treated with Crocin: The role of FOXO3a, PTEN and AKT signaling. Biochem. Pharm. 2020;177:113999.

    Not in our library10.1016/j.bcp.2020.113999

  68. 68.

    Shen L.D., Qi W.H., Bai J.J., Zuo C.Y., Bai D.L., Gao W.D., Zong X.L., Hao T.T., Ma Y., Cao G.C. Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation. Anat. Rec. 2021;304:313-322.

    Not in our library10.1002/ar.24378

  69. 69.

    Deng S., Shanmugam M.K., Kumar A.P., Yap C.T., Sethi G., Bishayee A. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer. 2019;125:1228-1246.

    Not in our library10.1002/cncr.31978

  70. 70.

    Patra S., Mishra S.R., Behera B.P., Mahapatra K.K., Panigrahi D.P., Bhol C.S., Praharaj P.P., Sethi G., Patra S.K., Bhutia S.K. Autophagy-modulating phytochemicals in cancer therapeutics: Current evidences and future perspectives. Semin. Cancer Biol. 2020.

    Not in our library10.1016/j.semcancer.2020.05.008

  71. 71.
    Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo · 2020
    No notice
  72. 72.

    Wang W., Dong X., Liu Y., Ni B., Sai N., You L., Sun M., Yao Y., Qu C., Yin X., et al. Itraconazole exerts anti-liver cancer potential through the Wnt, PI3K/AKT/mTOR, and ROS pathways. Biomed. Pharm. 2020;131:110661.

    Not in our library10.1016/j.biopha.2020.110661

  73. 73.

    Praharaj P.P., Naik P.P., Panigrahi D.P., Bhol C.S., Mahapatra K.K., Patra S., Sethi G., Bhutia S.K. Intricate role of mitochondrial lipid in mitophagy and mitochondrial apoptosis: Its implication in cancer therapeutics. Cell. Mol. Life Sci. 2019;76:1641-1652.

    Not in our library10.1007/s00018-018-2990-x

  74. 74.

    Chuang K.C., Chang C.R., Chang S.H., Huang S.W., Chuang S.M., Li Z.Y., Wang S.T., Kao J.K., Chen Y.J., Shieh J.J. Imiquimod-induced ROS production disrupts the balance of mitochondrial dynamics and increases mitophagy in skin cancer cells. J. Derm. Sci. 2020;98:152-162.

    Not in our library10.1016/j.jdermsci.2020.03.009

  75. 75.

    Choi H.J., Jhe Y.L., Kim J., Lim J.Y., Lee J.E., Shin M.K., Cheong J.H. FoxM1-dependent and fatty acid oxidation-mediated ROS modulation is a cell-intrinsic drug resistance mechanism in cancer stem-like cells. Redox Biol. 2020;36:101589.

    Not in our library10.1016/j.redox.2020.101589

  76. 76.

    Wang F., Wu H., Fan M., Yu R., Zhang Y., Liu J., Zhou X., Cai Y., Huang S., Hu Z., et al. Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells. FASEB J. 2020;34:4266-4282.

    Not in our library10.1096/fj.201902626r

  77. 77.

    Swetha K.L., Sharma S., Chowdhury R., Roy A. Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy. Pharm. Rep. 2020;72:1749-1765.

    Not in our library10.1007/s43440-020-00122-1

  78. 78.

    Wang H., Zhao L., Wu J., Hong J., Wang S. Propofol induces ROS-mediated intrinsic apoptosis and migration in triple-negative breast cancer cells. Oncol. Lett. 2020;20:810-816.

    Not in our library10.3892/ol.2020.11608

  79. 79.

    Oh H.N., Lee M.H., Kim E., Kwak A.W., Yoon G., Cho S.S., Liu K., Chae J.I., Shim J.H. Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET. Biomolecules. 2020;10:297.

    Not in our library10.3390/biom10020297

  80. 80.

    Zhu Q., Guo Y., Chen S., Fu D., Li Y., Li Z., Ni C. Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells. OncoTargets Ther. 2020;13:2807-2817.

    Not in our library10.2147/ott.s240803

  81. 81.

    Xiang H., Ramil C.P., Hai J., Zhang C., Wang H., Watkins A.A., Afshar R., Georgiev P., Sze M.A., Song X.S., et al. Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing ROS-Generating Monocytic MDSCs in Lung Squamous Cell Carcinoma. Cancer Immunol Res. 2020;8:436-450.

    Not in our library10.1158/2326-6066.cir-19-0507

  82. 82.

    Mo C.F., Li J., Yang S.X., Guo H.J., Liu Y., Luo X.Y., Wang Y.T., Li M.H., Li J.Y., Zou Q. IQGAP1 promotes anoikis resistance and metastasis through Rac1-dependent ROS accumulation and activation of Src/FAK signalling in hepatocellular carcinoma. Br. J. Cancer. 2020;123:1154-1163.

    Not in our library10.1038/s41416-020-0970-z

  83. 83.

    Nguyen D.J.M., Theodoropoulos G., Li Y.Y., Wu C., Sha W., Feun L.G., Lampidis T.J., Savaraj N., Wangpaichitr M. Targeting the Kynurenine Pathway for the Treatment of Cisplatin-Resistant Lung Cancer. Mol. Cancer Res. 2020;18:105-117.

    Not in our library10.1158/1541-7786.mcr-19-0239

  84. 84.

    Rowland B.D., Peeper D.S. KLF4, p21 and context-dependent opposing forces in cancer. Nat. Rev. Cancer. 2006;6:11-23.

    Not in our library10.1038/nrc1780

  85. 85.

    Zhang L., Li X., Chao Y., He R., Liu J., Yuan Y., Zhao W., Han C., Song X. KLF4, a miR-32-5p targeted gene, promotes cisplatin-induced apoptosis by upregulating BIK expression in prostate cancer. Cell Commun. Signal. 2018;16:53.

    Not in our library10.1186/s12964-018-0270-x

  86. 86.

    Yadav S.S., Kumar M., Varshney A., Yadava P.K. KLF4 sensitizes the colon cancer cell HCT-15 to cisplatin by altering the expression of HMGB1 and hTERT. Life Sci. 2019;220:169-176.

    Not in our library10.1016/j.lfs.2019.02.005

  87. 87.
    FBXW7 in Cancer: What Has Been Unraveled Thus Far? · 2019
    No notice
  88. 88.

    Abadi A.J., Zarrabi A., Gholami M.H., Mirzaei S., Hashemi F., Zabolian A., Entezari M., Hushmandi K., Ashrafizadeh M., Khan H. Small in Size, but Large in Action: MicroRNAs as Potential Modulators of PTEN in Breast and Lung Cancers. Biomolecules. 2021;11:304.

    Not in our library10.3390/biom11020304

  89. 89.

    Qi M.M., Ge F., Chen X.J., Tang C., Ma J. MiR-124 changes the sensitivity of lung cancer cells to cisplatin through targeting STAT3. Eur. Rev. Med. Pharm. Sci. 2019;23:5242-5250.

    Not in our library10.26355/eurrev_201906_18190

  90. 90.

    Jin L., Zhang Z. Serum miR-3180-3p and miR-124-3p may Function as Noninvasive Biomarkers of Cisplatin Resistance in Gastric Cancer. Clin. Lab. 2020;66.

    Not in our library10.7754/clin.lab.2020.200302

  91. 91.

    Xu Y., Lai Y., Weng H., Tan L., Li Y., Chen G., Luo X., Ye Y. MiR-124 sensitizes cisplatin-induced cytotoxicity against CD133(+) hepatocellular carcinoma cells by targeting SIRT1/ROS/JNK pathway. Aging. 2019;11:2551-2564.

    Not in our library10.18632/aging.101876

  92. 92.

    Pang Y., Mao H., Shen L., Zhao Z., Liu R., Liu P. MiR-519d represses ovarian cancer cell proliferation and enhances cisplatin-mediated cytotoxicity in vitro by targeting XIAP. OncoTargets Ther. 2014;7:587-597.

    Not in our library10.2147/ott.s60289

  93. 93.

    Xie Q., Wang S., Zhao Y., Zhang Z., Qin C., Yang X. MiR-519d impedes cisplatin-resistance in breast cancer stem cells by down-regulating the expression of MCL-1. Oncotarget. 2017;8:22003-22013.

    Not in our library10.18632/oncotarget.15781

  94. 94.

    Su X., Wang B., Wang Y., Wang B. Inhibition of TRIM32 Induced by miR-519d Increases the Sensitivity of Colorectal Cancer Cells to Cisplatin. OncoTargets Ther. 2020;13:277-289.

    Not in our library10.2147/ott.s235940

  95. 95.

    Yang H., Wu X.L., Wu K.H., Zhang R., Ju L.L., Ji Y., Zhang Y.W., Xue S.L., Zhang Y.X., Yang Y.F., et al. MicroRNA-497 regulates cisplatin chemosensitivity of cervical cancer by targeting transketolase. Am. J. Cancer Res. 2016;6:2690-2699.

    Not in our library

  96. 96.

    Chen G., Huang P., Hu C. The role of SIRT2 in cancer: A novel therapeutic target. Int. J. Cancer. 2020;147:3297-3304.

    Not in our library10.1002/ijc.33118

  97. 97.

    Wu S., Wang H., Pan Y., Yang X., Wu D. miR-140-3p enhances cisplatin sensitivity and attenuates stem cell-like properties through repressing Wnt/β-catenin signaling in lung adenocarcinoma cells. Exp. Med. 2020;20:1664-1674.

    Not in our library10.3892/etm.2020.8847

  98. 98.

    Du F., Li Z., Zhang G., Shaoyan S., Geng D., Tao Z., Qiu K., Liu S., Zhou Y., Zhang Y., et al. SIRT2, a direct target of miR-212-5p, suppresses the proliferation and metastasis of colorectal cancer cells. J. Cell Mol. Med. 2020;24:9985-9998.

    Not in our library10.1111/jcmm.15603

  99. 99.

    Cho H.Y., Thomas S., Golden E.B., Gaffney K.J., Hofman F.M., Chen T.C., Louie S.G., Petasis N.A., Schönthal A.H. Enhanced killing of chemo-resistant breast cancer cells via controlled aggravation of ER stress. Cancer Lett. 2009;282:87-97.

    Not in our library10.1016/j.canlet.2009.03.007

  100. 100.

    Shin S.Y., Lee J.M., Lee M.S., Koh D., Jung H., Lim Y., Lee Y.H. Targeting cancer cells via the reactive oxygen species-mediated unfolded protein response with a novel synthetic polyphenol conjugate. Clin. Cancer Res. 2014;20:4302-4313.

    Not in our library10.1158/1078-0432.ccr-14-0424

  101. 101.

    Jung E., Koh D., Lim Y., Shin S.Y., Lee Y.H. Overcoming multidrug resistance by activating unfolded protein response of the endoplasmic reticulum in cisplatin-resistant A2780/CisR ovarian cancer cells. BMB Rep. 2020;53:88-93.

    Not in our library10.5483/bmbrep.2020.53.2.108

  102. 102.

    Sun C., Guo E., Zhou B., Shan W., Huang J., Weng D., Wu P., Wang C., Wang S., Zhang W., et al. A reactive oxygen species scoring system predicts cisplatin sensitivity and prognosis in ovarian cancer patients. BMC Cancer. 2019;19:1061.

    Not in our library10.1186/s12885-019-6288-7

  103. 103.

    She Z.G., Chen H.Z., Yan Y., Li H., Liu D.P. The human paraoxonase gene cluster as a target in the treatment of atherosclerosis. Antioxid. Redox Signal. 2012;16:597-632.

    Not in our library10.1089/ars.2010.3774

  104. 104.

    Ng C.J., Wadleigh D.J., Gangopadhyay A., Hama S., Grijalva V.R., Navab M., Fogelman A.M., Reddy S.T. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J. Biol. Chem. 2001;276:44444-44449.

    Not in our library10.1074/jbc.m105660200

  105. 105.

    Précourt L.P., Marcil V., Ntimbane T., Taha R., Lavoie J.C., Delvin E., Seidman E.G., Beaulieu J.F., Levy E. Antioxidative properties of paraoxonase 2 in intestinal epithelial cells. Am. J. Physiol. Gastrointest Liver Physiol. 2012;303:G623-G634.

    Not in our library10.1152/ajpgi.00039.2012

  106. 106.

    Giordano G., Cole T.B., Furlong C.E., Costa L.G. Paraoxonase 2 (PON2) in the mouse central nervous system: A neuroprotective role? Toxicol. Appl. Pharm. 2011;256:369-378.

    Not in our library10.1016/j.taap.2011.02.014

  107. 107.

    Campagna R., Bacchetti T., Salvolini E., Pozzi V., Molinelli E., Brisigotti V., Sartini D., Campanati A., Ferretti G., Offidani A., et al. Paraoxonase-2 Silencing Enhances Sensitivity of A375 Melanoma Cells to Treatment with Cisplatin. Antioxidants. 2020;9:1238.

    Not in our library10.3390/antiox9121238

  108. 108.

    Liu Q., Wang K. The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin. Cell Biol. Int. 2019;43:1245-1256.

    Not in our library10.1002/cbin.11121

  109. 109.

    Koyama T., Suzuki H., Imakiire A., Yanase N., Hata K., Mizuguchi J. Id3-mediated enhancement of cisplatin-induced apoptosis in a sarcoma cell line MG-63. Anticancer Res. 2004;24:1519-1524.

    Not in our library

  110. 110.

    Narita N., Ito Y., Takabayashi T., Okamoto M., Imoto Y., Ogi K., Tokunaga T., Matsumoto H., Fujieda S. Suppression of SESN1 reduces cisplatin and hyperthermia resistance through increasing reactive oxygen species (ROS) in human maxillary cancer cells. Int. J. Hyperth. 2018;35:269-278.

    Not in our library10.1080/02656736.2018.1496282

  111. 111.

    Xue D.F., Pan S.T., Huang G., Qiu J.X. ROS enhances the cytotoxicity of cisplatin by inducing apoptosis and autophagy in tongue squamous cell carcinoma cells. Int. J. Biochem. Cell Biol. 2020;122:105732.

    Not in our library10.1016/j.biocel.2020.105732

  112. 112.
    Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells · 2019
    No notice
  113. 113.

    Lin Z., Pan J., Chen L., Wang X., Chen Y. MiR-140 Resensitizes Cisplatin-Resistant NSCLC Cells to Cisplatin Treatment Through the SIRT1/ROS/JNK Pathway. OncoTargets Ther. 2020;13:8149-8160.

    Not in our library10.2147/ott.s261799

  114. 114.

    Ciccarone F., De Falco P., Ciriolo M.R. Aconitase 2 sensitizes MCF-7 cells to cisplatin eliciting p53-mediated apoptosis in a ROS-dependent manner. Biochem. Pharm. 2020;180:114202.

    Not in our library10.1016/j.bcp.2020.114202

  115. 115.

    Roh J.L., Kim E.H., Jang H., Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017;11:254-262.

    Not in our library10.1016/j.redox.2016.12.010

  116. 116.

    Cruz-Bermúdez A., Laza-Briviesca R., Vicente-Blanco R.J., García-Grande A., Coronado M.J., Laine-Menéndez S., Palacios-Zambrano S., Moreno-Villa M.R., Ruiz-Valdepeñas A.M., Lendinez C., et al. Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition. Free Radic. Biol. Med. 2019;135:167-181.

    Not in our library10.1016/j.freeradbiomed.2019.03.009

  117. 117.

    He F., Antonucci L., Karin M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis. 2020;41:405-416.

    Not in our library10.1093/carcin/bgaa039

  118. 118.
    Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases · 2020
    No notice
  119. 119.

    Shin D., Kim E.H., Lee J., Roh J.L. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic. Biol. Med. 2018;129:454-462.

    Not in our library10.1016/j.freeradbiomed.2018.10.426

  120. 120.

    Luo P., Wu S., Ji K., Yuan X., Li H., Chen J., Tian Y., Qiu Y., Zhong X. LncRNA MIR4435-2HG mediates cisplatin resistance in HCT116 cells by regulating Nrf2 and HO-1. PLoS ONE. 2020;15:e0223035.

    Not in our library10.1371/journal.pone.0223035

  121. 121.

    Wang N., Song L., Xu Y., Zhang L., Wu Y., Guo J., Ji W., Li L., Zhao J., Zhang X., et al. Loss of Scribble confers cisplatin resistance during NSCLC chemotherapy via Nox2/ROS and Nrf2/PD-L1 signaling. EBioMedicine. 2019;47:65-77.

    Not in our library10.1016/j.ebiom.2019.08.057

  122. 122.
    The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling · 2020
    No notice
  123. 123.

    Fattahi S., Amjadi-Moheb F., Tabaripour R., Ashrafi G.H., Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci. 2020;262:118513.

    Not in our library10.1016/j.lfs.2020.118513

  124. 124.

    Lee J.H., Chinnathambi A., Alharbi S.A., Shair O.H.M., Sethi G., Ahn K.S. Farnesol abrogates epithelial to mesenchymal transition process through regulating Akt/mTOR pathway. Pharm. Res. 2019;150:104504.

    Not in our library10.1016/j.phrs.2019.104504

  125. 125.

    Lee J.H., Kim C., Um J.Y., Sethi G., Ahn K.S. Casticin-Induced Inhibition of Cell Growth and Survival Are Mediated through the Dual Modulation of Akt/mTOR Signaling Cascade. Cancers. 2019;11:254.

    Not in our library10.3390/cancers11020254

  126. 126.

    Wei X., Xu L., Jeddo S.F., Li K., Li X., Li J. MARK2 enhances cisplatin resistance via PI3K/AKT/NF-κB signaling pathway in osteosarcoma cells. Am. J. Transl. Res. 2020;12:1807-1823.

    Not in our library

  127. 127.

    Cao W.Q., Zhai X.Q., Ma J.W., Fu X.Q., Zhao B.S., Zhang P., Fu X.Y. Natural borneol sensitizes human glioma cells to cisplatin-induced apoptosis by triggering ROS-mediated oxidative damage and regulation of MAPKs and PI3K/AKT pathway. Pharm. Biol. 2020;58:72-79.

    Not in our library10.1080/13880209.2019.1703756

  128. 128.
    Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives · 2016
    No notice
  129. 129.

    Mohan C.D., Srinivasa V., Rangappa S., Mervin L., Mohan S., Paricharak S., Baday S., Li F., Shanmugam M.K., Chinnathambi A., et al. Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway. PLoS ONE. 2016;11:e0153155.

    Not in our library10.1371/journal.pone.0153155

  130. 130.

    Du H., Chen B., Jiao N.L., Liu Y.H., Sun S.Y., Zhang Y.W. Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma. Oxid. Med. Cell Longev. 2020;2020:7370157.

    Not in our library10.1155/2020/7370157

  131. 131.

    Zhang S., Wang Y. Deoxyshikonin inhibits cisplatin resistance of non-small-cell lung cancer cells by repressing Akt-mediated ABCB1 expression and function. J. Biochem. Mol. Toxicol. 2020;34:e22560.

    Not in our library10.1002/jbt.22560

  132. 132.

    Fan C.C., Tsai S.T., Lin C.Y., Chang L.C., Yang J.C., Chen G.Y., Sher Y.P., Wang S.C., Hsiao M., Chang W.C. EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis. Redox Biol. 2020;34:101571.

    Not in our library10.1016/j.redox.2020.101571

  133. 133.

    Wang Y., Hao F., Nan Y., Qu L., Na W., Jia C., Chen X. PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis. Int. J. Biol. Sci. 2018;14:1883-1891.

    Not in our library10.7150/ijbs.27854

  134. 134.

    Martin S.P., Fako V., Dang H., Dominguez D.A., Khatib S., Ma L., Wang H., Zheng W., Wang X.W. PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2020;39:99.

    Not in our library10.1186/s13046-020-01605-y

  135. 135.

    Shang D., Wu J., Guo L., Xu Y., Liu L., Lu J. Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2. Int. J. Oncol. 2017;50:1848-1856.

    Not in our library10.3892/ijo.2017.3950

  136. 136.

    Li W., Qiu Y., Hao J., Zhao C., Deng X., Shu G. Dauricine upregulates the chemosensitivity of hepatocellular carcinoma cells: Role of repressing glycolysis via miR-199a:HK2/PKM2 modulation. Food Chem. Toxicol. 2018;121:156-165.

    Not in our library10.1016/j.fct.2018.08.030

  137. 137.
    Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2 · 2021
    No notice
  138. 138.

    Powis G., Kirkpatrick D.L. Thioredoxin signaling as a target for cancer therapy. Curr. Opin. Pharm. 2007;7:392-397.

    Not in our library10.1016/j.coph.2007.04.003

  139. 139.

    Haas B., Schütte L., Wos-Maganga M., Weickhardt S., Timmer M., Eckstein N. Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. Int. J. Mol. Sci. 2018;19:2874.

    Not in our library10.3390/ijms19102874

  140. 140.

    Hong L., Chen J., Wu F., Wu F., Shen X., Zheng P., Shao R., Lu K., Liu Z., Chen D., et al. Isodeoxyelephantopin Inactivates Thioredoxin Reductase 1 and Activates ROS-Mediated JNK Signaling Pathway to Exacerbate Cisplatin Effectiveness in Human Colon Cancer Cells. Front. Cell Dev. Biol. 2020;8:580517.

    Not in our library10.3389/fcell.2020.580517

  141. 141.

    Wangpaichitr M., Sullivan E.J., Theodoropoulos G., Wu C., You M., Feun L.G., Lampidis T.J., Kuo M.T., Savaraj N. The relationship of thioredoxin-1 and cisplatin resistance: Its impact on ROS and oxidative metabolism in lung cancer cells. Mol. Cancer. 2012;11:604-615.

    Not in our library10.1158/1535-7163.mct-11-0599

  142. 142.

    Ashrafizadeh M., Zarrabi A., Hushmandi K., Hashemi F., Moghadam E.R., Owrang M., Hashemi F., Makvandi P., Goharrizi M.A.S.B., Najafi M., et al. Lung cancer cells and their sensitivity/resistance to cisplatin chemotherapy: Role of microRNAs and upstream mediators. Cell. Signal. 2021;78:109871.

    Not in our library10.1016/j.cellsig.2020.109871

  143. 143.

    Shang J., Wang L., Tan L., Pan R., Wu D., Xia Y., Xu P. MiR-27a-3p overexpression mitigates inflammation and apoptosis of lipopolysaccharides-induced alveolar epithelial cells by targeting FOXO3 and suppressing the activation of NAPDH/ROS. Biochem. Biophys. Res. Commun. 2020;533:723-731.

    Not in our library10.1016/j.bbrc.2020.07.126

  144. 144.

    Zhang Y., Xiao Y., Ma Y., Liang N., Liang Y., Lu C., Xiao F. ROS-mediated miR-21-5p regulates the proliferation and apoptosis of Cr(VI)-exposed L02 hepatocytes via targeting PDCD4. Ecotoxicol. Environ. Saf. 2020;191:110160.

    Not in our library10.1016/j.ecoenv.2019.110160

  145. 145.

    Maddalena F., Sisinni L., Lettini G., Condelli V., Matassa D.S., Piscazzi A., Amoroso M.R., La Torre G., Esposito F., Landriscina M. Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Mol. Oncol. 2013;7:895-906.

    Not in our library10.1016/j.molonc.2013.04.009

  146. 146.

    Cechetto J.D., Gupta R.S. Immunoelectron microscopy provides evidence that tumor necrosis factor receptor-associated protein 1 (TRAP-1) is a mitochondrial protein which also localizes at specific extramitochondrial sites. Exp. Cell Res. 2000;260:30-39.

    Not in our library10.1006/excr.2000.4983

  147. 147.

    Agorreta J., Hu J., Liu D., Delia D., Turley H., Ferguson D.J., Iborra F., Pajares M.J., Larrayoz M., Zudaire I. TRAP1 regulates proliferation, mitochondrial function, and has prognostic significance in NSCLC. Mol. Cancer Res. 2014;12:660-669.

    Not in our library10.1158/1541-7786.mcr-13-0481

  148. 148.

    Zhang X., Dong Y., Gao M., Hao M., Ren H., Guo L., Guo H. Knockdown of TRAP1 promotes cisplatin-induced apoptosis by promoting the ROS-dependent mitochondrial dysfunction in lung cancer cells. Mol. Cell Biochem. 2021;476:1075-1082.

    Not in our library10.1007/s11010-020-03973-7

  149. 149.

    Wek R.C., Jiang H.Y., Anthony T.G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 2006;34:7-11.

    Not in our library10.1042/bst0340007

  150. 150.

    Harding H.P., Zhang Y., Zeng H., Novoa I., Lu P.D., Calfon M., Sadri N., Yun C., Popko B., Paules R., et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell. 2003;11:619-633.

    Not in our library10.1016/s1097-2765(03)00105-9

  151. 151.

    Martínez-Reyes I., Sánchez-Aragó M., Cuezva J.M. AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells. Biochem. J. 2012;444:249-259.

    Not in our library10.1042/bj20111829

  152. 152.

    Rouschop K.M., Dubois L.J., Keulers T.G., van den Beucken T., Lambin P., Bussink J., van der Kogel A.J., Koritzinsky M., Wouters B.G. PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc. Natl. Acad. Sci. USA. 2013;110:4622-4627.

    Not in our library10.1073/pnas.1210633110

  153. 153.

    Wang S.F., Chen M.S., Chou Y.C., Ueng Y.F., Yin P.H., Yeh T.S., Lee H.C. Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway. Oncotarget. 2016;7:74132-74151.

    Not in our library10.18632/oncotarget.12356

  154. 154.

    Wang S.F., Wung C.H., Chen M.S., Chen C.F., Yin P.H., Yeh T.S., Chang Y.L., Chou Y.C., Hung H.H., Lee H.C. Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis. Int. J. Mol. Sci. 2018;19:3389.

    Not in our library10.3390/ijms19113389

  155. 155.

    De Franceschi L., Bertoldi M., De Falco L., Franco S.S., Ronzoni L., Turrini F., Colancecco A., Camaschella C., Cappellini M.D., Iolascon A. Oxidative stress modulates heme synthesis and induces peroxiredoxin-2 as a novel cytoprotective response in β-thalassemic erythropoiesis. Haematologica. 2011;96:1595.

    Not in our library10.3324/haematol.2011.043612

  156. 156.

    Wang S., Chen Z., Zhu S., Lu H., Peng D., Soutto M., Naz H., Peek R., Xu H., Zaika A., et al. PRDX2 protects against oxidative stress induced by H. pylori and promotes resistance to cisplatin in gastric cancer. Redox Biol. 2020;28:101319.

    Not in our library10.1016/j.redox.2019.101319

  157. 157.

    Lin X.M., Li S., Zhou C., Li R.Z., Wang H., Luo W., Huang Y.S., Chen L.K., Cai J.L., Wang T.X., et al. Cisplatin induces chemoresistance through the PTGS2-mediated anti-apoptosis in gastric cancer. Int. J. Biochem. Cell Biol. 2019;116:105610.

    Not in our library10.1016/j.biocel.2019.105610

  158. 158.

    Carreau A., Hafny-Rahbi B.E., Matejuk A., Grillon C., Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J. Cell. Mol. Med. 2011;15:1239-1253.

    Not in our library10.1111/j.1582-4934.2011.01258.x

  159. 159.
    Hypoxia and metabolic adaptation of cancer cells · 2016
    No notice
  160. 160.

    Ma Z., Wang L.Z., Cheng J.T., Lam W.S.T., Ma X., Xiang X., Wong A.L., Goh B.C., Gong Q., Sethi G., et al. Targeting Hypoxia-Inducible Factor-1-Mediated Metastasis for Cancer Therapy. Antioxid. Redox Signal. 2021.

    Not in our library10.1089/ars.2019.7935

  161. 161.

    Taguchi N., Ishihara N., Jofuku A., Oka T., Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J. Biol. Chem. 2007;282:11521-11529.

    Not in our library10.1074/jbc.m607279200

  162. 162.

    Archer S.L. Mitochondrial dynamics—Mitochondrial fission and fusion in human diseases. N. Engl. J. Med. 2013;369:2236-2251.

    Not in our library10.1056/nejmra1215233

  163. 163.

    Itoh K., Nakamura K., Iijima M., Sesaki H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 2013;23:64-71.

    Not in our library10.1016/j.tcb.2012.10.006

  164. 164.

    Han Y., Kim B., Cho U., Park I.S., Kim S.I., Dhanasekaran D.N., Tsang B.K., Song Y.S. Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene. 2019;38:7089-7105.

    Not in our library10.1038/s41388-019-0949-5

  165. 165.

    Wangpaichitr M., Kandemir H., Li Y.Y., Wu C., Nguyen D., Feun L.G., Kuo M.T., Savaraj N. Relationship of Metabolic Alterations and PD-L1 Expression in Cisplatin Resistant Lung Cancer. Cell Dev. Biol. 2017;6.

    Not in our library10.4172/2168-9296.1000183

  166. 166.

    Ohye H., Sugawara M. Dual oxidase, hydrogen peroxide and thyroid diseases. Exp. Biol. Med. 2010;235:424-433.

    Not in our library10.1258/ebm.2009.009241

  167. 167.

    Sandiford S.D., Kennedy K.A., Xie X., Pickering J.G., Li S.S. Dual oxidase maturation factor 1 (DUOXA1) overexpression increases reactive oxygen species production and inhibits murine muscle satellite cell differentiation. Cell Commun. Signal. 2014;12:5.

    Not in our library10.1186/1478-811x-12-5

  168. 168.

    Pichierri P., Rosselli F. The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. EMBO J. 2004;23:1178-1187.

    Not in our library10.1038/sj.emboj.7600113

  169. 169.

    Flynn R.L., Zou L. ATR: A master conductor of cellular responses to DNA replication stress. Trends Biochem. Sci. 2011;36:133-140.

    Not in our library10.1016/j.tibs.2010.09.005

  170. 170.

    Zhang Y., Hunter T. Roles of Chk1 in cell biology and cancer therapy. Int. J. Cancer. 2014;134:1013-1023.

    Not in our library10.1002/ijc.28226

  171. 171.

    Meng Y., Chen C.W., Yung M.M.H., Sun W., Sun J., Li Z., Li J., Li Z., Zhou W., Liu S.S., et al. DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer. Cancer Lett. 2018;428:104-116.

    Not in our library10.1016/j.canlet.2018.04.029

  172. 172.

    Greene K.S., Lukey M.J., Wang X., Blank B., Druso J.E., Lin M.J., Stalnecker C.A., Zhang C., Negrón Abril Y., Erickson J.W., et al. SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis. Proc. Natl. Acad. Sci. USA. 2019;116:26625-26632.

    Not in our library10.1073/pnas.1911954116

  173. 173.
    SIRT 5‐mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer · 2018
    No notice
  174. 174.

    Yang X., Wang Z., Li X., Liu B., Liu M., Liu L., Chen S., Ren M., Wang Y., Yu M., et al. SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation. Cancer Res. 2018;78:372-386.

    Not in our library10.1158/0008-5472.can-17-1912

  175. 175.

    Sun X., Wang S., Gai J., Guan J., Li J., Li Y., Zhao J., Zhao C., Fu L., Li Q. SIRT5 Promotes Cisplatin Resistance in Ovarian Cancer by Suppressing DNA Damage in a ROS-Dependent Manner via Regulation of the Nrf2/HO-1 Pathway. Front. Oncol. 2019;9:754.

    Not in our library10.3389/fonc.2019.00754

  176. 176.

    Xia M., Yu H., Gu S., Xu Y., Su J., Li H., Kang J., Cui M. p62/SQSTM1 is involved in cisplatin resistance in human ovarian cancer cells via the Keap1-Nrf2-ARE system. Int. J. Oncol. 2014;45:2341-2348.

    Not in our library10.3892/ijo.2014.2669

  177. 177.

    Shen L., Zhou L., Xia M., Lin N., Ma J., Dong D., Sun L. PGC1α regulates mitochondrial oxidative phosphorylation involved in cisplatin resistance in ovarian cancer cells via nucleo-mitochondrial transcriptional feedback. Exp. Cell Res. 2021;398:112369.

    Not in our library10.1016/j.yexcr.2020.112369

  178. 178.

    Chen J., Adikari M., Pallai R., Parekh H.K., Simpkins H. Dihydrodiol dehydrogenases regulate the generation of reactive oxygen species and the development of cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharm. 2008;61:979-987.

    Not in our library10.1007/s00280-007-0554-0

  179. 179.

    Shigeta K., Hasegawa M., Kikuchi E., Yasumizu Y., Kosaka T., Mizuno R., Mikami S., Miyajima A., Kufe D., Oya M. Role of the MUC1-C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma. Cancer Sci. 2020;111:3639-3652.

    Not in our library10.1111/cas.14574

  180. 180.

    Guo Y., Jia Y., Wang S., Liu N., Gao D., Zhang L., Lin Z., Wang S., Kong F., Peng C., et al. Downregulation of MUTYH contributes to cisplatin-resistance of esophageal squamous cell carcinoma cells by promoting Twist-mediated EMT. Oncol. Rep. 2019;42:2716-2727.

    Not in our library10.3892/or.2019.7347

  181. 181.

    Xiong P., Li Y.X., Tang Y.T., Chen H.G. Proteomic analyses of Sirt1-mediated cisplatin resistance in OSCC cell line. Protein J. 2011;30:499-508.

    Not in our library10.1007/s10930-011-9354-9

  182. 182.

    Shirato A., Kikugawa T., Miura N., Tanji N., Takemori N., Higashiyama S., Yokoyama M. Cisplatin resistance by induction of aldo-keto reductase family 1 member C2 in human bladder cancer cells. Oncol. Lett. 2014;7:674-678.

    Not in our library10.3892/ol.2013.1768

  183. 183.

    Hour T.C., Lai Y.L., Kuan C.I., Chou C.K., Wang J.M., Tu H.Y., Hu H.T., Lin C.S., Wu W.J., Pu Y.S., et al. Transcriptional up-regulation of SOD1 by CEBPD: A potential target for cisplatin resistant human urothelial carcinoma cells. Biochem. Pharm. 2010;80:325-334.

    Not in our library10.1016/j.bcp.2010.04.007

  184. 184.

    Zhang Z., Yu L., Dai G., Xia K., Liu G., Song Q., Tao C., Gao T., Guo W. Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells. Sci. Rep. 2017;7:7070.

    Not in our library10.1038/s41598-017-07204-w

  185. 185.

    Liu Y., Zhang Z., Li Q., Zhang L., Cheng Y., Zhong Z. Mitochondrial APE1 promotes cisplatin resistance by downregulating ROS in osteosarcoma. Oncol. Rep. 2020;44:499-508.

    Not in our library10.3892/or.2020.7633

  186. 186.

    Pan C., Jin L., Wang X., Li Y., Chun J., Boese A.C., Li D., Kang H.B., Zhang G., Zhou L., et al. Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance. J. Clin. Investig. 2019;129:2431-2445.

    Not in our library10.1172/jci124550

  187. 187.

    Geoghegan F., Buckland R.J., Rogers E.T., Khalifa K., O’Connor E.B., Rooney M.F., Behnam-Motlagh P., Nilsson T.K., Grankvist K., Porter R.K. Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells. Oncotarget. 2017;8:94711-94725.

    Not in our library10.18632/oncotarget.21885

  188. 188.

    Zheng X.L., Yang J.J., Wang Y.Y., Li Q., Song Y.P., Su M., Li J.K., Zhang L., Li Z.P., Zhou B., et al. RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells. Acta Pharmacol. Sin. 2020;41:1223-1233.

    Not in our library10.1038/s41401-019-0340-7

  189. 189.

    Muscella A., Vetrugno C., Antonaci G., Cossa L.G., Marsigliante S. PKC-δ/PKC-α activity balance regulates the lethal effects of cisplatin. Biochem. Pharm. 2015;98:29-40.

    Not in our library10.1016/j.bcp.2015.08.103

  190. 190.

    Songserm T., Pongrakhananon V., Chanvorachote P. Sub-toxic cisplatin mediates anoikis resistance through hydrogen peroxide-induced caveolin-1 up-regulation in non-small cell lung cancer cells. Anticancer Res. 2012;32:1659-1669.

    Not in our library

  191. 191.

    Su J., Xu Y., Zhou L., Yu H.M., Kang J.S., Liu N., Quan C.S., Sun L.K. Suppression of chloride channel 3 expression facilitates sensitivity of human glioma U251 cells to cisplatin through concomitant inhibition of Akt and autophagy. Anat. Rec. 2013;296:595-603.

    Not in our library10.1002/ar.22665

  192. 192.

    Kim C.W., Lu J.N., Go S.I., Jung J.H., Yi S.M., Jeong J.H., Hah Y.S., Han M.S., Park J.W., Lee W.S., et al. p53 restoration can overcome cisplatin resistance through inhibition of Akt as well as induction of Bax. Int. J. Oncol. 2013;43:1495-1502.

    Not in our library10.3892/ijo.2013.2070

  193. 193.

    Brockmueller A., Sameri S., Liskova A., Zhai K., Varghese E., Samuel S.M., Büsselberg D., Kubatka P., Shakibaei M. Resveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism. Cancers. 2021;13:188.

    Not in our library10.3390/cancers13020188

  194. 194.

    Samec M., Liskova A., Koklesova L., Samuel S.M., Zhai K., Buhrmann C., Varghese E., Abotaleb M., Qaradakhi T., Zulli A. Flavonoids against the Warburg phenotype—Concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism. EPMA J. 2020;1-22.

    Not in our library10.1007/s13167-020-00217-y

  195. 195.

    Zhai K., Brockmüller A., Kubatka P., Shakibaei M., Büsselberg D. Curcumin’s Beneficial Effects on Neuroblastoma: Mechanisms, Challenges, and Potential Solutions. Biomolecules. 2020;10:1469.

    Not in our library10.3390/biom10111469

  196. 196.

    Kubatka P., Kello M., Kajo K., Samec M., Liskova A., Jasek K., Koklesova L., Kuruc T., Adamkov M., Smejkal K. Rhus coriaria L.(Sumac) Demonstrates Oncostatic Activity in the Therapeutic and Preventive Model of Breast Carcinoma. Int. J. Mol. Sci. 2021;22:183.

    Not in our library10.3390/ijms22010183

  197. 197.

    Acuña-Castroviejo D., Escames G., Venegas C., Díaz-Casado M.E., Lima-Cabello E., López L.C., Rosales-Corral S., Tan D.X., Reiter R.J. Extrapineal melatonin: Sources, regulation, and potential functions. Cell. Mol. Life Sci. 2014;71:2997-3025.

    Not in our library10.1007/s00018-014-1579-2

  198. 198.

    Jadid M.F.S., Aghaei E., Taheri E., Seyyedsani N., Chavoshi R., Abbasi S., Khorrami A., Goleij P., Hajazimian S., Taefehshokr S., et al. Melatonin increases the anticancer potential of doxorubicin in Caco-2 colorectal cancer cells. Env. Toxicol. 2021.

    Not in our library10.1002/tox.23105

  199. 199.

    Plaimee P., Weerapreeyakul N., Barusrux S., Johns N.P. Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif. 2015;48:67-77.

    Not in our library10.1111/cpr.12158

  200. 200.

    Pariente R., Pariente J.A., Rodríguez A.B., Espino J. Melatonin sensitizes human cervical cancer HeLa cells to cisplatin-induced cytotoxicity and apoptosis: Effects on oxidative stress and DNA fragmentation. J. Pineal Res. 2016;60:55-64.

    Not in our library10.1111/jpi.12288

  201. 201.

    Long J., He Q., Yin Y., Lei X., Li Z., Zhu W. The effect of miRNA and autophagy on colorectal cancer. Cell Prolif. 2020;53:e12900.

    Not in our library10.1111/cpr.12900

  202. 202.

    Li J., Chen X., Kang R., Zeh H., Klionsky D.J., Tang D. Regulation and function of autophagy in pancreatic cancer. Autophagy. 2020;1-22.

    Not in our library10.1080/15548627.2020.1847462

  203. 203.
    High cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells · 2020
    No notice
  204. 204.
    Enterovirus 71 induces neural cell apoptosis and autophagy through promoting ACOX1 downregulation and ROS generation · 2020
    Not checked
  205. 205.

    Fernandez-Gil B.I., Guerra-Librero A., Shen Y.Q., Florido J., Martínez-Ruiz L., García-López S., Adan C., Rodríguez-Santana C., Acuña-Castroviejo D., Quiñones-Hinojosa A., et al. Melatonin Enhances Cisplatin and Radiation Cytotoxicity in Head and Neck Squamous Cell Carcinoma by Stimulating Mitochondrial ROS Generation, Apoptosis, and Autophagy. Oxid. Med. Cell Longev. 2019;2019:7187128.

    Not in our library10.1155/2019/7187128

  206. 206.

    Yin X., Yang G., Ma D., Su Z. Inhibition of cancer cell growth in cisplatin-resistant human oral cancer cells by withaferin-A is mediated via both apoptosis and autophagic cell death, endogenous ROS production, G2/M phase cell cycle arrest and by targeting MAPK/RAS/RAF signalling pathway. J. Buon. 2020;25:332-337.

    Not in our library

  207. 207.

    Jin Y., Huang R., Xia Y., Huang C., Qiu F., Pu J., He X., Zhao X. Long Noncoding RNA KIF9-AS1 Regulates Transforming Growth Factor-β and Autophagy Signaling to Enhance Renal Cell Carcinoma Chemoresistance via microRNA-497-5p. DNA Cell Biol. 2020;39:1096-1103.

    Not in our library10.1089/dna.2020.5453

  208. 208.

    Manu K.A., Shanmugam M.K., Ong T.H., Subramaniam A., Siveen K.S., Perumal E., Samy R.P., Bist P., Lim L.H., Kumar A.P., et al. Emodin suppresses migration and invasion through the modulation of CXCR4 expression in an orthotopic model of human hepatocellular carcinoma. PLoS ONE. 2013;8:e57015.

    Not in our library10.1371/journal.pone.0057015

  209. 209.

    Subramaniam A., Loo S.Y., Rajendran P., Manu K.A., Perumal E., Li F., Shanmugam M.K., Siveen K.S., Park J.I., Ahn K.S., et al. An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins. Apoptosis. 2013;18:1175-1187.

    Not in our library10.1007/s10495-013-0851-5

  210. 210.

    Bai J., Wu J., Tang R., Sun C., Ji J., Yin Z., Ma G., Yang W. Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR(2) and miR-34a. Investig. New Drugs. 2020;38:229-245.

    Not in our library10.1007/s10637-019-00777-5

  211. 211.

    Ding N., Zhang H., Su S., Ding Y., Yu X., Tang Y., Wang Q., Liu P. Emodin Enhances the Chemosensitivity of Endometrial Cancer by Inhibiting ROS-Mediated Cisplatin-resistance. Anticancer Agents Med. Chem. 2018;18:1054-1063.

    Not in our library10.2174/1871520618666171219113036

  212. 212.

    Li X., Wang H., Wang J., Chen Y., Yin X., Shi G., Li H., Hu Z., Liang X. Emodin enhances cisplatin-induced cytotoxicity in human bladder cancer cells through ROS elevation and MRP1 downregulation. BMC Cancer. 2016;16:578.

    Not in our library10.1186/s12885-016-2640-3

  213. 213.

    Zhu B., Ren C., Du K., Zhu H., Ai Y., Kang F., Luo Y., Liu W., Wang L., Xu Y., et al. Olean-28,13b-olide 2 plays a role in cisplatin-mediated apoptosis and reverses cisplatin resistance in human lung cancer through multiple signaling pathways. Biochem. Pharm. 2019;170:113642.

    Not in our library10.1016/j.bcp.2019.113642

  214. 214.

    Kim E.H., Jang H., Shin D., Baek S.H., Roh J.L. Targeting Nrf2 with wogonin overcomes cisplatin resistance in head and neck cancer. Apoptosis. 2016;21:1265-1278.

    Not in our library10.1007/s10495-016-1284-8

  215. 215.

    Kim E.H., Jang H., Roh J.L. A Novel Polyphenol Conjugate Sensitizes Cisplatin-Resistant Head and Neck Cancer Cells to Cisplatin via Nrf2 Inhibition. Mol. Cancer. 2016;15:2620-2629.

    Not in our library10.1158/1535-7163.mct-16-0332

  216. 216.

    Huang W.L., Wu S.F., Xu S.T., Ma Y.C., Wang R., Jin S., Zhou S. Allicin enhances the radiosensitivity of colorectal cancer cells via inhibition of NF-κB signaling pathway. J. Food Sci. 2020;85:1924-1931.

    Not in our library10.1111/1750-3841.15156

  217. 217.

    Wu H., Li X., Zhang T., Zhang G., Chen J., Chen L., He M., Hao B., Wang C. Overexpression miR-486-3p Promoted by Allicin Enhances Temozolomide Sensitivity in Glioblastoma Via Targeting MGMT. Neuromol. Med. 2020;22:359-369.

    Not in our library10.1007/s12017-020-08592-5

  218. 218.

    Țigu A.B., Toma V.A., Moț A.C., Jurj A., Moldovan C.S., Fischer-Fodor E., Berindan-Neagoe I., Pârvu M. The Synergistic Antitumor Effect of 5-Fluorouracil Combined with Allicin against Lung and Colorectal Carcinoma Cells. Molecules. 2020;25:1947.

    Not in our library10.3390/molecules25081947

  219. 219.

    Pandey N., Tyagi G., Kaur P., Pradhan S., Rajam M.V., Srivastava T. Allicin Overcomes Hypoxia Mediated Cisplatin Resistance in Lung Cancer Cells through ROS Mediated Cell Death Pathway and by Suppressing Hypoxia Inducible Factors. Cell Physiol. Biochem. 2020;54:748-766.

    Not in our library10.33594/000000253

  220. 220.

    Kośmider A., Czepielewska E., Kuraś M., Gulewicz K., Pietrzak W., Nowak R., Nowicka G. Uncaria tomentosa Leaves Decoction Modulates Differently ROS Production in Cancer and Normal Cells, and Effects Cisplatin Cytotoxicity. Molecules. 2017;22:620.

    Not in our library10.3390/molecules22040620

  221. 221.

    Yang H., Zhu J., Wang G., Liu H., Zhou Y., Qian J. STK35 Is Ubiquitinated by NEDD4L and Promotes Glycolysis and Inhibits Apoptosis Through Regulating the AKT Signaling Pathway, Influencing Chemoresistance of Colorectal Cancer. Front. Cell Dev. Biol. 2020;8:582695.

    Not in our library10.3389/fcell.2020.582695

  222. 222.

    Gao J., Dai C., Yu X., Yin X.B., Zhou F. Long noncoding RNA LEF1-AS1 acts as a microRNA-10a-5p regulator to enhance MSI1 expression and promote chemoresistance in hepatocellular carcinoma cells through activating AKT signaling pathway. J. Cell. Biochem. 2021;122:86-99.

    Not in our library10.1002/jcb.29833

  223. 223.

    Zhang C., Lin T., Nie G., Hu R., Pi S., Wei Z., Wang C., Xing C., Hu G. Cadmium and molybdenum co-induce pyroptosis via ROS/PTEN/PI3K/AKT axis in duck renal tubular epithelial cells. Environ. Pollut. 2021;272:116403.

    Not in our library10.1016/j.envpol.2020.116403

  224. 224.

    Wang L., Wang L., Shi X., Xu S. Chlorpyrifos induces the apoptosis and necroptosis of L8824 cells through the ROS/PTEN/PI3K/AKT axis. J. Hazard. Mater. 2020;398:122905.

    Not in our library10.1016/j.jhazmat.2020.122905

  225. 225.

    Zhang C., He L.J., Zhu Y.B., Fan Q.Z., Miao D.D., Zhang S.P., Zhao W.Y., Liu X.P. Piperlongumine Inhibits Akt Phosphorylation to Reverse Resistance to Cisplatin in Human Non-Small Cell Lung Cancer Cells via ROS Regulation. Front. Pharmacol. 2019;10:1178.

    Not in our library10.3389/fphar.2019.01178

  226. 226.

    Zhang Y., Zheng S., Zheng J.S., Wong K.H., Huang Z., Ngai S.M., Zheng W., Wong Y.S., Chen T. Synergistic induction of apoptosis by methylseleninic acid and cisplatin, the role of ROS-ERK/AKT-p53 pathway. Mol. Pharm. 2014;11:1282-1293.

    Not in our library10.1021/mp400749f

  227. 227.

    He G., He G., Zhou R., Pi Z., Zhu T., Jiang L., Xie Y. Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo. Biochem. Biophys. Res. Commun. 2016;469:1075-1082.

    Not in our library10.1016/j.bbrc.2015.12.100

  228. 228.

    Petroni G., Bagni G., Iorio J., Duranti C., Lottini T., Stefanini M., Kragol G., Becchetti A., Arcangeli A. Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K. Cell Death Dis. 2020;11:161.

    Not in our library10.1038/s41419-020-2349-8

  229. 229.

    Zhou B., Xia M., Wang B., Thapa N., Gan L., Sun C., Guo E., Huang J., Lu Y., Cai H. Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo. J. Ovarian Res. 2019;12:107.

    Not in our library10.1186/s13048-019-0570-9

  230. 230.

    Davra V., Kumar S., Geng K., Calianese D., Mehta D., Gadiyar V., Kasikara C., Lahey K.C., Chang Y.J., Wichroski M., et al. Axl and Mertk receptors cooperate to promote breast cancer progression by combined oncogenic signaling and evasion of host anti-tumor immunity. Cancer Res. 2020.

    Not in our library10.1158/0008-5472.can-20-2066

  231. 231.

    Lotsberg M.L., Wnuk-Lipinska K., Terry S., Tan T.Z., Lu N., Trachsel-Moncho L., Røsland G.V., Siraji M.I., Hellesøy M., Rayford A., et al. AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells. J. Thorac. Oncol. 2020;15:973-999.

    Not in our library10.1016/j.jtho.2020.01.015

  232. 232.

    Tian M., Chen X.S., Li L.Y., Wu H.Z., Zeng D., Wang X.L., Zhang Y., Xiao S.S., Cheng Y. Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis. Acta Pharmacol. Sin. 2020.

    Not in our library10.1038/s41401-020-00546-8

  233. 233.

    Oien D.B., Garay T., Eckstein S., Chien J. Cisplatin and Pemetrexed Activate AXL and AXL Inhibitor BGB324 Enhances Mesothelioma Cell Death from Chemotherapy. Front. Pharmacol. 2017;8:970.

    Not in our library10.3389/fphar.2017.00970

  234. 234.

    Piotrowska A., Wierzbicka J., Rybarczyk A., Tuckey R.C., Slominski A.T., Żmijewski M.A. Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line. Int. J. Oncol. 2019;54:1481-1495.

    Not in our library10.3892/ijo.2019.4725

  235. 235.

    Xue D., Pan S.T., Zhou X., Ye F., Zhou Q., Shi F., He F., Yu H., Qiu J. Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma. Oxid. Med. Cell Longev. 2020;2020:5649174.

    Not in our library10.1155/2020/5649174

  236. 236.

    Xie C., Zhang L.Z., Chen Z.L., Zhong W.J., Fang J.H., Zhu Y., Xiao M.H., Guo Z.W., Zhao N., He X., et al. A hMTR4-PDIA3P1-miR-125/124-TRAF6 Regulatory Axis and Its Function in NF kappa B Signaling and Chemoresistance. Hepatology. 2020;71:1660-1677.

    Not in our library10.1002/hep.30931

  237. 237.

    Zhong Y.Y., Chen H.P., Tan B.Z., Yu H.H., Huang X.S. Triptolide avoids cisplatin resistance and induces apoptosis via the reactive oxygen species/nuclear factor-κB pathway in SKOV3(PT) platinum-resistant human ovarian cancer cells. Oncol. Lett. 2013;6:1084-1092.

    Not in our library10.3892/ol.2013.1524

  238. 238.
    Ascorbate sensitizes human osteosarcoma cells to the cytostatic effects of cisplatin · 2020
    Not checked
  239. 239.

    Roh J.L., Park J.Y., Kim E.H., Jang H.J., Kwon M. Activation of mitochondrial oxidation by PDK2 inhibition reverses cisplatin resistance in head and neck cancer. Cancer Lett. 2016;371:20-29.

    Not in our library10.1016/j.canlet.2015.11.023

  240. 240.

    Petruzzella E., Sirota R., Solazzo I., Gandin V., Gibson D. Triple action Pt(iv) derivatives of cisplatin: A new class of potent anticancer agents that overcome resistance. Chem. Sci. 2018;9:4299-4307.

    Not in our library10.1039/c8sc00428e

  241. 241.

    Huang Z., Yang G., Shen T., Wang X., Li H., Ren D. Dehydrobruceine B enhances the cisplatin-induced cytotoxicity through regulation of the mitochondrial apoptotic pathway in lung cancer A549 cells. Biomed. Pharm. 2017;89:623-631.

    Not in our library10.1016/j.biopha.2017.02.055

  242. 242.

    Lee M.R., Lin C., Lu C.C., Kuo S.C., Tsao J.W., Juan Y.N., Chiu H.Y., Lee F.Y., Yang J.S., Tsai F.J. YC-1 induces G(0)/G(1) phase arrest and mitochondria-dependent apoptosis in cisplatin-resistant human oral cancer CAR cells. Biomedicine. 2017;7:12.

    Not in our library10.1051/bmdcn/2017070205

  243. 243.

    Altaf M., Monim-Ul-Mehboob M., Kawde A.N., Corona G., Larcher R., Ogasawara M., Casagrande N., Celegato M., Borghese C., Siddik Z.H., et al. New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status. Oncotarget. 2017;8:490-505.

    Not in our library10.18632/oncotarget.13448

  244. 244.

    Wangpaichitr M., Wu C., You M., Maher J.C., Dinh V., Feun L.G., Savaraj N. N’,N’-Dimethyl-N’,N’-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS). Cancers. 2009;1:23-38.

    Not in our library10.3390/cancers1010023

  245. 245.

    Zeng L., Chen Y., Liu J., Huang H., Guan R., Ji L., Chao H. Ruthenium(II) Complexes with 2-Phenylimidazo[4,5-f][1,10]phenanthroline Derivatives that Strongly Combat Cisplatin-Resistant Tumor Cells. Sci. Rep. 2016;6:19449.

    Not in our library10.1038/srep19449

  246. 246.

    Chen L., Liu L., Li Y., Gao J. Melatonin increases human cervical cancer HeLa cells apoptosis induced by cisplatin via inhibition of JNK/Parkin/mitophagy axis. Vitr. Cell. Dev. Biol. Anim. 2018;54:1-10.

    Not in our library10.1007/s11626-017-0200-z

  247. 247.

    Shaaban S., Shabana S.M., Al-Faiyz Y.S., Manolikakes G., El-Senduny F.F. Enhancing the chemosensitivity of HepG2 cells towards cisplatin by organoselenium pseudopeptides. Bioorganic Chem. 2021;109:104713.

    Not in our library10.1016/j.bioorg.2021.104713

  248. 248.

    Xiao Y., Deng T., Wang D. Davanone terpenoid inhibits cisplatin-resistant acute myeloid leukemia cancer cell growth by inducing caspase-dependent apoptosis, loss of mitochondrial membrane potential, inhibition of cell migration and invasion and targeting PI3K/AKT/MAPK signalling pathway. J. Buon. 2020;25:1607-1613.

    Not in our library

  249. 249.

    Hassanvand F., Mohammadi T., Ayoubzadeh N., Tavakoli A., Hassanzadeh N., Sanikhani N.S., Azimi A.I., Mirzaei H.R., Khodamoradi M., Goudarzi K.A., et al. Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells. J. Cancer Res. 2020;16:1412-1418.

    Not in our library10.4103/jcrt.jcrt_675_19

  250. 250.

    Hu X., Wang J., Chai J., Yu X., Zhang Y., Feng Y., Qin J., Yu H. Chaetomugilin J Enhances Apoptosis in Human Ovarian Cancer A2780 Cells Induced by Cisplatin Through Inhibiting Pink1/Parkin Mediated Mitophagy. OncoTargets Ther. 2020;13:9967-9976.

    Not in our library10.2147/ott.s273435

  251. 251.

    Pattarawat P., Hong T., Wallace S., Hu Y., Donnell R., Wang T.H., Tsai C.L., Wang J., Wang H.R. Compensatory combination of romidepsin with gemcitabine and cisplatin to effectively and safely control urothelial carcinoma. Br. J. Cancer. 2020;123:226-239.

    Not in our library10.1038/s41416-020-0877-8

  252. 252.

    Chen F., Qin X., Xu G., Gou S., Jin X. Reversal of cisplatin resistance in human gastric cancer cells by a wogonin-conjugated Pt(IV) prodrug via attenuating Casein Kinase 2-mediated Nuclear Factor-κB pathways. Biochem. Pharm. 2017;135:50-68.

    Not in our library10.1016/j.bcp.2017.03.004

  253. 253.

    Lin Y.H., Chen B.Y., Lai W.T., Wu S.F., Guh J.H., Cheng A.L., Hsu L.C. The Akt inhibitor MK-2206 enhances the cytotoxicity of paclitaxel (Taxol) and cisplatin in ovarian cancer cells. Naunyn Schmiedebergs Arch. Pharm. 2015;388:19-31.

    Not in our library10.1007/s00210-014-1032-y

  254. 254.

    Chan D.W., Yung M.M., Chan Y.S., Xuan Y., Yang H., Xu D., Zhan J.B., Chan K.K., Ng T.B., Ngan H.Y. MAP30 protein from Momordica charantia is therapeutic and has synergic activity with cisplatin against ovarian cancer in vivo by altering metabolism and inducing ferroptosis. Pharm. Res. 2020;161:105157.

    Not in our library10.1016/j.phrs.2020.105157

  255. 255.

    Yang Z., Guo F., Albers A.E., Sehouli J., Kaufmann A.M. Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed. Pharm. 2019;113:108727.

    Not in our library10.1016/j.biopha.2019.108727

  256. 256.

    Pluchino L.A., Choudhary S., Wang H.C. Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of clonogenic resistance in breast cancer cells by combined cisplatin and FK228. Cancer Lett. 2016;381:124-132.

    Not in our library10.1016/j.canlet.2016.07.036

  257. 257.

    Huang X., Wang M., Wang C., Hu W., You Q., Yang Y., Yu C., Liao Z., Gou S., Wang H. Dual-targeting antitumor conjugates derived from platinum(IV) prodrugs and microtubule inhibitor CA-4 significantly exhibited potent ability to overcome cisplatin resistance. Bioorg. Chem. 2019;92:103236.

    Not in our library10.1016/j.bioorg.2019.103236

  258. 258.

    Mai L., Luo M., Wu J.J., Yang J.H., Hong L.Y. The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells. Neoplasma. 2019;66:776-784.

    Not in our library10.4149/neo_2018_180921n708

  259. 259.

    Almotairy A.R.Z., Montagner D., Morrison L., Devereux M., Howe O., Erxleben A. Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells. J. Inorg. Biochem. 2020;210:111125.

    Not in our library10.1016/j.jinorgbio.2020.111125

  260. 260.

    Xu Y., Gao W., Zhang Y., Wu S., Liu Y., Deng X., Xie L., Yang J., Yu H., Su J., et al. ABT737 reverses cisplatin resistance by targeting glucose metabolism of human ovarian cancer cells. Int. J. Oncol. 2018;53:1055-1068.

    Not in our library10.3892/ijo.2018.4476

  261. 261.

    Yang Y.I., Ahn J.H., Choi Y.S., Choi J.H. Brown algae phlorotannins enhance the tumoricidal effect of cisplatin and ameliorate cisplatin nephrotoxicity. Gynecol. Oncol. 2015;136:355-364.

    Not in our library10.1016/j.ygyno.2014.11.015

  262. 262.

    Ayyagari V.N., Hsieh T.J., Diaz-Sylvester P.L., Brard L. Evaluation of the cytotoxicity of the Bithionol—Cisplatin combination in a panel of human ovarian cancer cell lines. BMC Cancer. 2017;17:49.

    Not in our library10.1186/s12885-016-3034-2

  263. 263.

    Ma J., Yang J., Wang C., Zhang N., Dong Y., Wang C., Wang Y., Lin X. Emodin augments cisplatin cytotoxicity in platinum-resistant ovarian cancer cells via ROS-dependent MRP1 downregulation. Biomed. Res. Int. 2014;2014:107671.

    Not in our library10.1155/2014/107671

  264. 264.

    Zhang P., Zhao S., Lu X., Shi Z., Liu H., Zhu B. Metformin enhances the sensitivity of colorectal cancer cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway. Gene. 2020;745:144623.

    Not in our library10.1016/j.gene.2020.144623

  265. 265.

    Lee Y., Kim Y.J., Choi Y.J., Lee J.W., Lee S., Chung H.W. Enhancement of cisplatin cytotoxicity by benzyl isothiocyanate in HL-60 cells. Food Chem. Toxicol. 2012;50:2397-2406.

    Not in our library10.1016/j.fct.2012.04.014

  266. 266.

    Qu X., Sheng J., Shen L., Su J., Xu Y., Xie Q., Wu Y., Zhang X., Sun L. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS. PLoS ONE. 2017;12:e0173712.

    Not in our library10.1371/journal.pone.0173712

  267. 267.

    Hsin I.L., Wang S.C., Li J.R., Ciou T.C., Wu C.H., Wu H.M., Ko J.L. Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death via autophagy for resensitizing cisplatin-resistant urothelial cancer cells. Phytomedicine. 2016;23:1566-1573.

    Not in our library10.1016/j.phymed.2016.09.003

  268. 268.

    Nur G., Nazıroğlu M., Deveci H.A. Synergic prooxidant, apoptotic and TRPV1 channel activator effects of alpha-lipoic acid and cisplatin in MCF-7 breast cancer cells. J. Recept Signal. Transduct Res. 2017;37:569-577.

    Not in our library10.1080/10799893.2017.1369121

  269. 269.

    Sivalingam K.S., Paramasivan P., Weng C.F., Viswanadha V.P. Neferine Potentiates the Antitumor Effect of Cisplatin in Human Lung Adenocarcinoma Cells Via a Mitochondria-Mediated Apoptosis Pathway. J. Cell. Biochem. 2017;118:2865-2876.

    Not in our library10.1002/jcb.25937

  270. 270.

    Zhu Z. Miltirone-induced apoptosis in cisplatin-resistant lung cancer cells through upregulation of p53 signaling pathways. Oncol. Lett. 2018;15:8841-8846.

    Not in our library10.3892/ol.2018.8440

  271. 271.

    Yu N., Xiong Y., Wang C. Bu-Zhong-Yi-Qi Decoction, the Water Extract of Chinese Traditional Herbal Medicine, Enhances Cisplatin Cytotoxicity in A549/DDP Cells through Induction of Apoptosis and Autophagy. Biomed. Res. Int. 2017;2017:3692797.

    Not in our library10.1155/2017/3692797

  272. 272.

    Liu X., Wang W., Yin Y., Li M., Li H., Xiang H., Xu A., Mei X., Hong B., Lin W. A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer. Investig. New Drugs. 2019;37:1166-1176.

    Not in our library10.1007/s10637-019-00750-2

  273. 273.

    Wang R., Ma L., Weng D., Yao J., Liu X., Jin F. Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway. Oncol. Rep. 2016;35:3075-3083.

    Not in our library10.3892/or.2016.4690

  274. 274.

    Chen T.J., Zhou Y.F., Ning J.J., Yang T., Ren H., Li Y., Zhang S., Chen M.W. NBM-T-BMX-OS01, an Osthole Derivative, Sensitizes Human Lung Cancer A549 Cells to Cisplatin through AMPK-Dependent Inhibition of ERK and Akt Pathway. Cell Physiol. Biochem. 2015;36:893-906.

    Not in our library10.1159/000430264

  275. 275.

    Lou J.S., Yan L., Bi C.W., Chan G.K., Wu Q.Y., Liu Y.L., Huang Y., Yao P., Du C.Y., Dong T.T., et al. Yu Ping Feng San reverses cisplatin-induced multi-drug resistance in lung cancer cells via regulating drug transporters and p62/TRAF6 signalling. Sci. Rep. 2016;6:31926.

    Not in our library10.1038/srep31926

  276. 276.

    Park B.H., Lim J.E., Jeon H.G., Seo S.I., Lee H.M., Choi H.Y., Jeon S.S., Jeong B.C. Curcumin potentiates antitumor activity of cisplatin in bladder cancer cell lines via ROS-mediated activation of ERK1/2. Oncotarget. 2016;7:63870-63886.

    Not in our library10.18632/oncotarget.11563

  277. 277.

    Liao X.Z., Tao L.T., Liu J.H., Gu Y.Y., Xie J., Chen Y., Lin M.G., Liu T.L., Wang D.M., Guo H.Y., et al. Matrine combined with cisplatin synergistically inhibited urothelial bladder cancer cells via down-regulating VEGF/PI3K/Akt signaling pathway. Cancer Cell Int. 2017;17:124.

    Not in our library10.1186/s12935-017-0495-6

  278. 278.

    Gan D., He W., Yin H., Gou X. β-elemene enhances cisplatin-induced apoptosis in bladder cancer cells through the ROS-AMPK signaling pathway. Oncol. Lett. 2020;19:291-300.

    Not in our library10.3892/ol.2019.11103

  279. 279.

    Kakar S.S., Jala V.R., Fong M.Y. Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem. Biophys. Res. Commun. 2012;423:819-825.

    Not in our library10.1016/j.bbrc.2012.06.047

  280. 280.

    El-Senduny F.F., Badria F.A., El-Waseef A.M., Chauhan S.C., Halaweish F. Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B. Tumour Biol. 2016;37:685-698.

    Not in our library10.1007/s13277-015-3773-8

  281. 281.

    Gökçe Kütük S., Gökçe G., Kütük M., Gürses Cila H.E., Nazıroğlu M. Curcumin enhances cisplatin-induced human laryngeal squamous cancer cell death through activation of TRPM2 channel and mitochondrial oxidative stress. Sci. Rep. 2019;9:17784.

    Not in our library10.1038/s41598-019-54284-x

  282. 282.

    Tayeh Z., Ofir R. Asteriscus graveolens Extract in Combination with Cisplatin/Etoposide/Doxorubicin Suppresses Lymphoma Cell Growth through Induction of Caspase-3 Dependent Apoptosis. Int. J. Mol. Sci. 2018;19:2219.

    Not in our library10.3390/ijms19082219

  283. 283.

    Liu Y.S., Li H.S., Qi D.F., Zhang J., Jiang X.C., Shi K., Zhang X.J., Zhang X.H. Zinc protoporphyrin IX enhances chemotherapeutic response of hepatoma cells to cisplatin. World J. Gastroenterol. 2014;20:8572-8582.

    Not in our library10.3748/wjg.v20.i26.8572

  284. 284.

    Tan J., Song M., Zhou M., Hu Y. Antibiotic tigecycline enhances cisplatin activity against human hepatocellular carcinoma through inducing mitochondrial dysfunction and oxidative damage. Biochem. Biophys. Res. Commun. 2017;483:17-23.

    Not in our library10.1016/j.bbrc.2017.01.021

  285. 285.

    Deng H., Ma J., Liu Y., He P., Dong W. Combining α-Hederin with cisplatin increases the apoptosis of gastric cancer in vivo and in vitro via mitochondrial related apoptosis pathway. Biomed. Pharm. 2019;120:109477.

    Not in our library10.1016/j.biopha.2019.109477

  286. 286.

    Liu Y., Lei H., Ma J., Deng H., He P., Dong W. α-Hederin Increases The Apoptosis Of Cisplatin-Resistant Gastric Cancer Cells By Activating Mitochondrial Pathway In Vivo And Vitro. OncoTargets Ther. 2019;12:8737-8750.

    Not in our library10.2147/ott.s221005

  287. 287.

    Shin J.I., Jeon Y.J., Lee S., Lee Y.G., Kim J.B., Lee K. G-Protein-Coupled Receptor 120 Mediates DHA-Induced Apoptosis by Regulating IP3R, ROS and, ER Stress Levels in Cisplatin-Resistant Cancer Cells. Mol. Cells. 2019;42:252-261.

    Not in our library10.14348/molcells.2019.2440

  288. 288.

    Liu Y., Qin L., Bi T., Dai W., Liu W., Gao Q., Shen G. Oxymatrine Synergistically Potentiates the Antitumor Effects of Cisplatin in Human Gastric Cancer Cells. J. Cancer. 2018;9:4527-4535.

    Not in our library10.7150/jca.28532

  289. 289.

    Lee Y.J., Lee G.J., Yi S.S., Heo S.H., Park C.R., Nam H.S., Cho M.K., Lee S.H. Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells. Food Chem. Toxicol. 2016;97:96-107.

    Not in our library10.1016/j.fct.2016.08.033

  290. 290.

    Hammouda M.B., Riahi-Chebbi I., Souid S., Othman H., Aloui Z., Srairi-Abid N., Karoui H., Gasmi A., Magnenat E.M., Wells T.N.C., et al. Macrovipecetin, a C-type lectin from Macrovipera lebetina venom, inhibits proliferation migration and invasion of SK-MEL-28 human melanoma cells and enhances their sensitivity to cisplatin. Biochim. Biophys. Acta Gen. Subj. 2018;1862:600-614.

    Not in our library10.1016/j.bbagen.2017.11.019

  291. 291.

    Allegra M., D’Anneo A., Frazzitta A., Restivo I., Livrea M.A., Attanzio A., Tesoriere L. The Phytochemical Indicaxanthin Synergistically Enhances Cisplatin-Induced Apoptosis in HeLa Cells via Oxidative Stress-Dependent p53/p21(waf1) Axis. Biomolecules. 2020;10:994.

    Not in our library10.3390/biom10070994

  292. 292.

    Kim E.H., Baek S., Shin D., Lee J., Roh J.L. Hederagenin Induces Apoptosis in Cisplatin-Resistant Head and Neck Cancer Cells by Inhibiting the Nrf2-ARE Antioxidant Pathway. Oxid. Med. Cell Longev. 2017;2017:5498908.

    Not in our library10.1155/2017/5498908

  293. 293.

    Ye S.F., Yang Y., Wu L., Ma W.W., Zeng H.H. Ethaselen: A novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis. J. Zhejiang Univ. Sci. B. 2017;18:373-382.

    Not in our library10.1631/jzus.b1600073

  294. 294.

    Su S., Dou H., Wang Z., Zhang Q. Bufalin inhibits ovarian carcinoma via targeting mTOR/HIF-α pathway. Basic Clin. Pharm. Toxicol. 2021;128:224-233.

    Not in our library10.1111/bcpt.13487

  295. 295.

    Liu Y., Wang X., Li W., Xu Y., Zhuo Y., Li M., He Y., Wang X., Guo Q., Zhao L., et al. Oroxylin A reverses hypoxia-induced cisplatin resistance through inhibiting HIF-1α mediated XPC transcription. Oncogene. 2020;39:6893-6905.

    Not in our library10.1038/s41388-020-01474-x

  296. 296.

    Zhu J., Li B., Xu M., Liu R., Xia T., Zhang Z., Xu Y., Liu S. Graphene Oxide Promotes Cancer Metastasis through Associating with Plasma Membrane To Promote TGF-β Signaling-Dependent Epithelial-Mesenchymal Transition. ACS Nano. 2020;14:818-827.

    Not in our library10.1021/acsnano.9b07891

  297. 297.

    Song Y., Zou X., Zhang D., Liu S., Duan Z., Liu L. Self-enforcing HMGB1/NF-κB/HIF-1α Feedback Loop Promotes Cisplatin Resistance in Hepatocellular Carcinoma Cells. J. Cancer. 2020;11:3893-3902.

    Not in our library10.7150/jca.42944

  298. 298.

    Bejjanki N.K., Xu H., Xie M. GSH triggered intracellular aggregated-cisplatin-loaded iron oxide nanoparticles for overcoming cisplatin resistance in nasopharyngeal carcinoma. J. Biomater. Appl. 2021;885328220982151.

    Not in our library10.1177/0885328220982151

  299. 299.

    Yu M., Ozaki T., Sun D., Xing H., Wei B., An J., Yang J., Gao Y., Liu S., Kong C., et al. HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4. J. Exp. Clin. Cancer Res. 2020;39:108.

    Not in our library10.1186/s13046-020-01613-y

  300. 300.

    Zhang Q., Zhang H., Ning T., Liu D., Deng T., Liu R., Bai M., Zhu K., Li J., Fan Q., et al. Exosome-Delivered c-Met siRNA Could Reverse Chemoresistance to Cisplatin in Gastric Cancer. Int. J. Nanomed. 2020;15:2323-2335.

    Not in our library10.2147/ijn.s231214

  301. 301.

    Wu B., Yuan Y., Han X., Wang Q., Shang H., Liang X., Jing H., Cheng W. Structure of LINC00511-siRNA-conjugated nanobubbles and improvement of cisplatin sensitivity on triple negative breast cancer. FASEB J. 2020;34:9713-9726.

    Not in our library10.1096/fj.202000481r

  302. 302.

    Gu J., Li Y., Zeng J., Wang B., Ji K., Tang Y., Sun Q. Knockdown of HIF-1α by siRNA-expressing plasmid delivered by attenuated Salmonella enhances the antitumor effects of cisplatin on prostate cancer. Sci. Rep. 2017;7:7546.

    Not in our library10.1038/s41598-017-07973-4

  303. 303.

    Lou J.S., Zhao L.P., Huang Z.H., Chen X.Y., Xu J.T., Tai W.C., Tsim K.W.K., Chen Y.T., Xie T. Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine. 2021;80:153370.

    Not in our library10.1016/j.phymed.2020.153370

  304. 304.

    Kim H.R., Kim S., Kim E.J., Park J.H., Yang S.H., Jeong E.T., Park C., Youn M.J., So H.S., Park R. Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin. Lung Cancer. 2008;60:47-56.

    Not in our library10.1016/j.lungcan.2007.09.021

  305. 305.

    Delfi M., Sartorius R., Ashrafizadeh M., Sharifi E., Zhang Y., De Berardinis P., Zarrabi A., Varma R.S., Tay F.R., Smith B.R., et al. Self-assembled peptide and protein nanostructures for anti-cancer therapy: Targeted delivery, stimuli-responsive devices and immunotherapy. Nano Today. 2021;38:101119.

    Not in our library10.1016/j.nantod.2021.101119

  306. 306.

    Ashrafizadeh M., Delfi M., Hashemi F., Zabolian A., Saleki H., Bagherian M., Azami N., Farahani M.V., Sharifzadeh S.O., Hamzehlou S., et al. Biomedical application of chitosan-based nanoscale delivery systems: Potential usefulness in siRNA delivery for cancer therapy. Carbohydr. Polym. 2021;260:117809.

    Not in our library10.1016/j.carbpol.2021.117809

  307. 307.

    Xue X., Hall M.D., Zhang Q., Wang P.C., Gottesman M.M., Liang X.-J. Nanoscale drug delivery platforms overcome platinum-based resistance in cancer cells due to abnormal membrane protein trafficking. ACS Nano. 2013;7:10452-10464.

    Not in our library10.1021/nn405004f

  308. 308.

    Bidram E., Esmaeili Y., Ranji-Burachaloo H., Al-Zaubai N., Zarrabi A., Stewart A., Dunstan D.E. A concise review on cancer treatment methods and delivery systems. J. Drug Deliv. Sci. Technol. 2019;54:101350.

    Not in our library10.1016/j.jddst.2019.101350

  309. 309.

    Huang X., Chen J., Wu W., Yang W., Zhong B., Qing X., Shao Z. Delivery of MutT homolog 1 inhibitor by functionalized graphene oxide nanoparticles for enhanced chemo-photodynamic therapy triggers cell death in osteosarcoma. Acta Biomater. 2020;109:229-243.

    Not in our library10.1016/j.actbio.2020.04.009

  310. 310.

    Lima-Sousa R., de Melo-Diogo D., Alves C.G., Cabral C.S.D., Miguel S.P., Mendonça A.G., Correia I.J. Injectable in situ forming thermo-responsive graphene based hydrogels for cancer chemo-photothermal therapy and NIR light-enhanced antibacterial applications. Mater. Sci. Eng. C Mater. Biol. Appl. 2020;117:111294.

    Not in our library10.1016/j.msec.2020.111294

  311. 311.

    Zhang W., Shen J., Su H., Mu G., Sun J.H., Tan C.P., Liang X.J., Ji L.N., Mao Z.W. Co-Delivery of Cisplatin Prodrug and Chlorin e6 by Mesoporous Silica Nanoparticles for Chemo-Photodynamic Combination Therapy to Combat Drug Resistance. ACS Appl. Mater. Interfaces. 2016;8:13332-13340.

    Not in our library10.1021/acsami.6b03881

  312. 312.

    Qian G., Wang L., Zheng X., Yu T. Deactivation of cisplatin-resistant human lung/ovary cancer cells with pyropheophorbide-α methyl ester-photodynamic therapy. Cancer Biol. 2017;18:984-989.

    Not in our library10.1080/15384047.2017.1385683

  313. 313.
    Mode of photoexcited C60 fullerene involvement in potentiating cisplatin toxicity against drug-resistant L1210 cells · 2019
    Not checked
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    Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways · 2021
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    Yang T., Yu S., Liu L., Sun Y., Lan Y., Ma X., Zhu R., Li L., Hou Y., Liu Y. Dual polymeric prodrug co-assembled nanoparticles with precise ratiometric co-delivery of cisplatin and metformin for lung cancer chemoimmunotherapy. Biomater. Sci. 2020;8:5698-5714.

    Not in our library10.1039/d0bm01191f

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    Saber M.M., Al-Mahallawi A.M., Nassar N.N., Stork B., Shouman S.A. Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes. BMC Cancer. 2018;18:822.

    Not in our library10.1186/s12885-018-4727-5

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    Pourbagher-Shahri A.M., Farkhondeh T., Ashrafizadeh M., Talebi M., Samargahndian S. Curcumin and cardiovascular diseases: Focus on cellular targets and cascades. Biomed. Pharmacother. 2021;136:111214.

    Not in our library10.1016/j.biopha.2020.111214

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    Curcumin and Colorectal Cancer: From Basic to Clinical Evidences · 2020
    No notice
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    Farkhondeh T., Ashrafizadeh M., Azimi-Nezhad M., Samini F., Aschenr M., Samarghandian S. Curcumin Efficacy in a Serum/glucose Deprivation-induced Neuronal PC12 Injury Model. Curr. Mol. Pharmacol. 2021.

    Not in our library10.2174/1874467214666210203211312

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    Curcumin Delivery Mediated by Bio-Based Nanoparticles: A Review · 2020
    No notice
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    Tewari D., Nabavi S.F., Nabavi S.M., Sureda A., Farooqi A.A., Atanasov A.G., Vacca R.A., Sethi G., Bishayee A. Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention. Pharm. Res. 2018;128:366-375.

    Not in our library10.1016/j.phrs.2017.09.014

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    Hong Y., Che S., Hui B., Wang X., Zhang X., Ma H. Combination Therapy of Lung Cancer Using Layer-by-Layer Cisplatin Prodrug and Curcumin Co-Encapsulated Nanomedicine. Drug Des. Dev. 2020;14:2263-2274.

    Not in our library10.2147/dddt.s241291

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    Abdul Satar N., Ismail M.N., Yahaya B.H. Synergistic Roles of Curcumin in Sensitising the Cisplatin Effect on a Cancer Stem Cell-Like Population Derived from Non-Small Cell Lung Cancer Cell Lines. Molecules. 2021;26:1056.

    Not in our library10.3390/molecules26041056

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    Cheng Y., Zhao P., Wu S., Yang T., Chen Y., Zhang X., He C., Zheng C., Li K., Ma X., et al. Cisplatin and curcumin co-loaded nano-liposomes for the treatment of hepatocellular carcinoma. Int. J. Pharm. 2018;545:261-273.

    Not in our library10.1016/j.ijpharm.2018.05.007

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    Chang P.Y., Peng S.F., Lee C.Y., Lu C.C., Tsai S.C., Shieh T.M., Wu T.S., Tu M.G., Chen M.Y., Yang J.S. Curcumin-loaded nanoparticles induce apoptotic cell death through regulation of the function of MDR1 and reactive oxygen species in cisplatin-resistant CAR human oral cancer cells. Int. J. Oncol. 2013;43:1141-1150.

    Not in our library10.3892/ijo.2013.2050

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    Sun M., He L., Fan Z., Tang R., Du J. Effective treatment of drug-resistant lung cancer via a nanogel capable of reactivating cisplatin and enhancing early apoptosis. Biomaterials. 2020;257:120252.

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    Raviadaran R., Ng M.H., Chandran D., Ooi K.K., Manickam S. Stable W/O/W multiple nanoemulsion encapsulating natural tocotrienols and caffeic acid with cisplatin synergistically treated cancer cell lines (A549 and HEP G2) and reduced toxicity on normal cell line (HEK 293). Mater. Sci. Eng. C Mater. Biol. Appl. 2021;121:111808.

    Not in our library10.1016/j.msec.2020.111808

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    Badea M.A., Prodana M., Dinischiotu A., Crihana C., Ionita D., Balas M. Cisplatin Loaded Multiwalled Carbon Nanotubes Induce Resistance in Triple Negative Breast Cancer Cells. Pharmaceutics. 2018;10:228.

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    Li F., Li T., Cao W., Wang L., Xu H. Near-infrared light stimuli-responsive synergistic therapy nanoplatforms based on the coordination of tellurium-containing block polymer and cisplatin for cancer treatment. Biomaterials. 2017;133:208-218.

    Not in our library10.1016/j.biomaterials.2017.04.032

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    Wang X., Gong Q., Song C., Fang J., Yang Y., Liang X., Huang X., Liu J. Berberine-photodynamic therapy sensitizes melanoma cells to cisplatin-induced apoptosis through ROS-mediated P38 MAPK pathways. Toxicol. Appl. Pharm. 2021;115484.

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    Xiang J., Li Y., Zhang Y., Wang G., Xu H., Zhou Z., Tang J., Shen Y. Polyphenol-cisplatin complexation forming core-shell nanoparticles with improved tumor accumulation and dual-responsive drug release for enhanced cancer chemotherapy. J. Control. Release. 2021;330:992-1003.

    Not in our library10.1016/j.jconrel.2020.11.006

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    Shi D., Zhang Y., Tian Y. SLAMF1 Promotes Methotrexate Resistance via Activating Autophagy in Choriocarcinoma Cells. Cancer Manag. Res. 2020;12:13427-13436.

    Not in our library10.2147/cmar.s278012

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