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A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging

Annet Nicole Linders, Itamar Braga Dias, Teresa López Fernández and 3 more

npj Aging · 2024 · Review · CC BY

doi:10.1038/s41514-024-00135-7

Abstract

The population of cancer survivors is rapidly increasing due to improving healthcare. However, cancer therapies often have long-term side effects. One example is cancer therapy-related cardiac dysfunction (CTRCD) caused by doxorubicin: up to 9% of the cancer patients treated with this drug develop heart failure at a later stage. In recent years, doxorubicin-induced cardiotoxicity has been associated with an accelerated aging phenotype and cellular senescence in the heart. In this review we explain the evidence of an accelerated aging phenotype in the doxorubicin-treated heart by comparing it to healthy aged hearts, and shed light on treatment strategies that are proposed in pre-clinical settings. We will discuss the accelerated aging phenotype and the impact it could have in the clinic and future research.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

In recent years, the number of cancer survivors has increased. In Europe alone, 12 million patients were successfully treated for cancer. Among this group, the long-term cardiac side-effects of cancer therapies are becoming evident. Between 1 and 5% of cancer survivors show signs of cancer therapy-related cardiac dysfunction (CTRCD), and 20% of these patients show asymptomatic LV function reduction,. In childhood cancer survivors who reached the age of 50, this percentage was even higher. The cumulative incidence of at least one symptom of cardiovascular disease was 45.5%, while this was only 15.7% in controls,. One of the chemotherapeutic drugs that is notorious for causing CTRCD, is doxorubicin. Doxorubicin-induced cardiotoxicity (DCT) is defined by a decline in left ventricular ejection fraction of more than 10% to a value smaller than 53%,. This happens in up to 9% of the patient population treated with doxorubicin, depending on the received cumulative dose,.

The mechanisms underlying DCT are extensively investigated, but no conclusive evidence has been found. Proposed mechanisms include apoptosis, mitochondrial dysfunction, calcium dysregulation, inflammation, and oxidative stress,. One hypothesis that is supported by an increasing pool of evidence, is that doxorubicin causes a phenotype of accelerated aging, resulting to changes in the mentioned processes–. This is illustrated by studies in patients who were treated with doxorubicin during their childhood. These individuals show physical traits that are more similar to an older population, in terms of frailty, endurance, development of life-threatening diseases, and muscle strength,,. Aging is also visible at the cellular level, where it is termed cellular senescence,–.

Doxorubicin: molecular and biological characteristics of a potent cancer treatment

Doxorubicin was discovered in 1969 as a homolog of daunorubicin, and was isolated from a soil bacterium, Streptomyces peucetius,. It is a widely used chemotherapeutic drug to treat solid tumors, leukemia, and lymphoma both in adults and children. The classic antitumor effect of doxorubicin is most often attributed to the inhibition of Topoisomerase IIb (TOP2B). TOP2B is an enzyme that prevents double stranded nuclear DNA breaks (DSBs) caused by stresses in the strands. These can build up due to transcription or replication. Besides this, doxorubicin is involved in many other mechanisms directly and indirectly underlying DSBs, such as increased reactive oxygen species (ROS) production and mitochondrial dysfunction.

Implementation of doxorubicin in cancer treatment regimens has been very beneficial, as reflected by the reduced the risk of death in ovarian cancer by 15% (HR = 0.85 [CI 0.76–0.95], p < 0.001). In metastatic breast cancer, doxorubicin led to a survival advantage of 13% (HR = 1.13 [CI 1.00–1.27]). However, by this time it was also evident that doxorubicin could cause cardiotoxicity in a dose dependent manner. In a large meta-analysis, 22,815 doxorubicin-treated patients, 17.9% of these patients developed sub-clinical cardiac dysfunction, while 6.3% of them developed clinical heart failure. Cumulative dose was reported as the most important predictor of DCT.

Many mechanisms for DCT have been proposed. However, controversy remains due to varying doses of doxorubicin used in preclinical experiments. In human blood, the concentration after doxorubicin administration is typically between 0.025 and 0.250 µmol/L–, whereas in vitro experiments often apply doses of 1 µmol/L or higher. Additionally, mice can tolerate much higher doxorubicin concentrations, with tolerable blood concentrations reaching 0.7–2.1 µmol/L (10–30 mg/kg),. Doxorubicin treatment has shown different pharmacological effects at different concentrations: At sub-micromolar concentrations, the primary mechanism of action is on DSB formation, while this shifts to free radical toxicity at 2–4 µmol/L. Therefore, the accelerated aging phenotype might have been overlooked in experimental setups assessing cardiomyopathy.

Phenotypic overlap between the aged and the doxorubicin-treated heart

As the heart ages, it undergoes many transformations, affecting morphology, electrophysiology gene expression, and metabolism, all of which have a substantial influence on cardiac output. Particularly, the heart of a patient with DCT exhibits more similarities with the heart of an aged individual than with that of healthy peers,,. Both the aged and DCT heart show decreased atrial emptying rates, a measure of diastolic dysfunction–. This is linked to development of atrial fibrillation (AF)– Incidence of AF increases with age: below the age of 55, 0.1–0.2% of the population has AF, while this number increases to 9.1–11.1% above 85 years,. In DCT patients (46 ± 15 years), the incidence of atrial fibrillation lies around 10%,. Additionally, both the aged and DCT treated heart show prolonged QT intervals, pointing at aberrant electrophysiology,,.

On a morphological level, hypertrophy was observed in experimental models of both the aged– and the DCT heart–, as well as in patients when measuring LV mass index,,. When assessed microscopically, both the aged and DCT heart show accumulation of waste products, shown with lipofuscin staining and increased β-galactosidase activity,,–. Furthermore, increased fibrosis is observed (1.5x increase in the aged heart, 2.2x increase in the DCT heart,). In DCT mRNA expression of collagen fibers is not upregulated, while protein levels are increased. Besides, cardiac fibroblasts show increased expression of matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs), suggesting increased remodeling,,. Inhibition of MMPs during doxorubicin treatment prevents DCT.

Overall, there are marked similarities between aged and, often younger, DCT hearts, supporting the hypothesis that doxorubicin induces an accelerated aging phenotype.

Molecular consequences: cellular senescence as a hallmark of the aging process

The aging of the human body is accompanied by increasing numbers of senescent cells. Increased senescent cells are found in DCT models as well, for example in a transgenic model that permits the identification of cells expressing p16, a regulator of senescence. Various cell types in the heart have been shown to become senescent upon doxorubicin treatment, including cardiomyocytes, endothelial cells, cardiac fibroblasts, and cardiac progenitor cells. While our primary focus is on cardiomyocytes, many of the processes described here are also applicable to the other cell types (Fig. 1).

DNA damage and double-stranded break repair

DNA is a very stable molecule: intact DNA molecules of 700,000 years old have been recovered. However, it is common knowledge that DNA damage arises on a day-to-day basis in several forms, including formation of oxidized nucleotides, single strand breaks, double strand breaks, and inter-strand crosslinks. The cell protects itself from the cytotoxic effects, by activating DNA damage response (DDR), which also consists of a range of mechanisms. These include base excision repair, non-homologous end-joining, and homologous recombination. Which of these is used depends on the type of damage and the speed and accuracy at which the DNA needs to be repaired. All these levels of protection cannot prevent accumulation of permanent mutations over time. Doxorubicin also accelerates the DNA mutation rate. by interacting with DNA in two ways: by intercalating with the strands–, or by inhibiting TOP2b as mentioned above–. When doxorubicin intercalates with the DNA, it preferably binds to areas rich in GC basepairs. The complex that is formed leads to supercoiling of the DNA strands, which results in increased stresses and the unwrapping of the DNA from the nucleosome. The relevance of this mechanism in patients can be questioned, since only 4–5 adducts form every 107 base pairs at clinically relevant doses. There is more evidence for the activity of the second mechanism within patients, inhibition of TOP2b. Doxorubicin can influence TOP2b in two ways: it can prevent the protein from binding to the DNA or it can inhibit the final ligation step,,. Inhibition of binding is due to the intercalation of doxorubicin with the DNA, but this does not happen in relevant frequency at clinical doses. Thus, the second mechanism is a more likely candidate. When TOP2b is knocked out both in vitro, and in vivo, DCT can be prevented–. Additional confirmation of role of TOP2b in DCT comes from the use of dexrazoxane. Dexrazoxane administration simultaneously with doxorubicin has shown reduction of DCT incidence. Initially, it was believed that dexrazoxane mitigated DCT through iron chelation, but recent research indicates that it depletes TOP2a and TOP2b from tissues, thereby protecting the heart from toxicity,.

DNA damage activates senescence-related pathways. The first proteins that react to DNA damage are Ataxia Telangiectasia Mutated (ATM), Ataxia Telangiectasia and Rad3-Related Protein (ATR), and Checkpoint Kinase 1 (Chk1) and 2 (Chk2). ATM-Chk2 is activated by double stranded breaks, while ATR-Chk1 reacts to single stranded breaks. Inhibition of the cell cycle is accomplished through p53. In the healthy cell, p53 is a short-lived protein, which is rapidly ubiquitinated by Mouse Double Minute 2 homolog (MDM2) and MDM4 and degraded. ATM-Chk2 and ATR-Chk1 affect p53 in multiple ways. First, they stabilize it by inhibiting MDM2 and MDM4. Secondly, they also phosphorylate p53. Once phosphorylated, p53 can either activate p53 upregulated modulator of apoptosis (PUMA) and NOXA, which are apoptosis regulators, or p21, which causes cellular senescence. How it is determined which pathway is activated is not fully understood, but Forkhead box protein O4 (FOXO4) is believed to be involved. Disruption of p53-FOXO4 complexes with a peptide causes senescent cells to go into apoptosis. Another important senescence marker that activates upon DNA stress, independently from p53, is p16. Although postnatal cardiomyocytes are in cell cycle arrest at the G1/S restriction point, they show upregulation of these pathways regardless,, (Fig. 2).

Another regulator of senescence is p38MAPK. It can be activated by DNA damage, oxidative stress, ER stress, metabolic stress, and inflammatory stress. When activated, it can drive many other pathways, including p53, p21 (independent of p53), p16, and NF-kB pathways. Treatment with doxorubicin has been shown to activate p38MAPK,.

Telomeres

In addition to DNA damage, aging correlates with telomere shortening. To replicate DNA, DNA polymerase needs an RNA primer as a starting position. At the ends of the DNA strands, this results in the loss of basepairs with each replication cycle (the end replication problem). To protect the genetic material, the ends of chromosomes consist of telomeres. These are repeats of a random sequence, packaged in protein complexes known as shelterin. Shelterin prevents the recognition of chromosome ends as DNA damage. With every replication, the telomeres become shorter, until they reach a critical length that disrupts the shelterin complex. This activates a sustained DDR and the cell stops proliferating. Telomerase can lengthen the telomeres again, but it is not expressed in all celltypes. In a study of 530 autopsy subjects, it was shown that telomeres in the heart shorten at a rate of approximately 20 basepairs per year. With age, an increase in DDR proteins was observed in the telomeres, independent from shortening,. In doxorubicin-treated human and mouse hearts, telomeres were shorter compared to controls. Telomere binding proteins and telomerase were also shown to be dysregulated in doxorubicin-treated hearts.

Epigenetics

DNA in the nucleus is wrapped around proteins (histones) and organized into chromosomes. Modification of packaging can control gene expression: tightly packed DNA cannot be transcribed (heterochromatin), while loosely organized DNA is available for transcription (euchromatin). The tightness of packaging is adjusted by modifications of the histones and of the DNA itself. Acetylation promotes formation of euchromatin, while methylation promotes heterochromatin. Aging reduces histone levels and when they are experimentally elevated, lifespan is increased. Doxorubicin treatment causes nucleosome turnover around the promoters of active genes and histone eviction and degradation, resulting in decreased cellular histone levels.

DNA bases can be methylated, mostly in CpG islands: stretches of DNA less than 200 basepairs long, which contain >50% C-G pairs. CpG islands are often located in proximity to promotors. More methylated bases results in decreased gene expression. Aging leads to an overall decrease of DNA methylation. Doxorubicin decreases expression of DNA methyltransferases, and methylation levels,. Methylation levels can be used to determine biological age, which has been linked to cardiovascular health–. Although DNA methylation in doxorubicin-treated models has been measured, biological age has not been assessed.

Epigenetic regulation ties gene expression to metabolism. During aging and doxorubicin treatment availability of substrates such as ATP, NAD+, and acetyl co-enzyme declines, resulting in heterochromatin,. Sirtuins, NAD+ dependent histone deacetylases, are regulators of this process. When there is less energy, more NAD+ is available, and Sirtiuns deacetylate histones, leading to heterochromatin. The involvement of these proteins in aging and DCT has been studied extensively. Overexpression of several Sirtuins increased lifespan, while knockout decreased lifespan,. Several studies showed increased activity of Sirtuins protects the heart from DCT,,–.

Mitochondrial dysfunction and mtDNA damage

Due to high energy demand, 40% of the cardiomyocyte’s cytoplasm is occupied by mitochondria, Mitochondrial dysfunction, a primary characteristic of senescence, therefore plays a key role in cardiomyocytes. Improving mitochondrial function can suppress senescence. Mitochondria have an inner (IMM) and an outer (OMM) mitochondrial membrane. In the IMM, the electron transport chain (ETC) is present consisting of four complexes (complex I-IV) that use NADH and oxygen to increase the proton content in the intermembrane compartment. ATP synthase (complex V) uses this gradient to phosphorylate ADP into ATP (oxidative phosphorylation). The IMM is folded into cristae, to increase the surface area available for oxidative phosphorylation. During aging, organization of these cristae is disrupted, and the activity of the ETC is decreased,. Both are a result of changing phospholipid content of the IMM and the resulting decreased membrane fluidity. This disrupts the organization of the ETC complexes, interrupting efficient function. Cardiolipin, a phospholipid exclusive to the IMM, is a likely candidate. Its conical structure enables the membrane to form curves. Cardiolipin content decreases with age and experimental addition of it to aged mitochondria increased function,. Doxorubicin accumulates in mitochondria, partially by binding to cardiolipin,. The phospholipid has an anionic charge, while doxorubicin has a cationic charge, resulting in the formation of acomplex,. Similar to aged-induced dysfunction, this bond disrupts the organization of the cristae,– and inhibits proper function of ETC. Other processes that are affected in aged cells include a shift to glycolysis, increased proton leak, decreased membrane potential, and increased ROS production,,,. These changes also take place in doxorubicin-treated cells,,,,,,,–. In senescent fibroblasts, mitochondrial function decreased, possibly due to impaired mitophagy. Doxorubicin-treated fibroblasts show a similar phenotype, possibly mediated by p53. Mitochondria have small circular mitochondrial DNA (mtDNA) strands. mtDNA encodes a few proteins, which all are involved in ATP-production. There are less repair mechanisms in place for mtDNA, therefore the mutation rate is 10–17 times higher than in nuclear DNA. Over time, mutation in the mtDNA accumulate, resulting in mitochondrial dysfunction. The role of mtDNA in aging was confirmed in a mouse-model expressing a defective mitochondrial DNA polymerase: it showed an accelerated aging phenotype,. Doxorubicin is a molecule that can interact with DNA. It increases mutation rate and dysfunction of mitochondria,.

Reactive oxygen species and oxidative stress

Mitochondria are a source of free radicals such as ROS. In a healthy cell, there is a balance between the production of free radicals and the activity of antioxidant enzymes and molecules. However, when this balance is disrupted, the cell will enter a state of oxidative stress. The heart is particularly vulnerable to oxidative stress, due to high metabolic activity, production of radicals for signaling purposes, and low amounts of antioxidants and antioxidant enzymes,,. The presence of free radicals causes sulfhydryl oxidation, lipid peroxidation, cardiolipin reduction, and mtDNA damage in the mitochondria. This leads to a further increase in free radical production. Free radicals can cross over to organelles that are in close proximity, such as the endoplasmatic reticulum. The cell will respond by uncoupling the oxidative phosphorylation from ATP production (proton leak), increasing activity of the ETC complexes,. It has been shown that both aging processes and doxorubicin treatment increases ROS production in cardiomyocytes, and cardiac fibroblasts,.

During aging, the activity of the ETC complexes decreases. This increases ROS molecule production. In doxorubicin-treated cells, activity of the ETC also decreases with similar results. Besides that, doxorubicin is a quinone molecule which can be reduced by several enzymes, including cytosolic xanthine oxidase, NADH dehydrogenase (complex I), and NADPH-dependent cytochrome P450 reductases. After reduction, it auto-oxidizes to its neutral state. During this second step, a superoxide anion is generated,. Doxorubicin also reduces expression of antioxidant enzymes,.

Overall, it can be concluded that ROS production increases in both aging cells and in doxorubicin-treated cells. In recent years, several studies suggest that increasing ROS may not be the causative factor of both aging and DCT. While suppression of ROS production is beneficial in aged animal models, in the healthy aged population suppression of ROS production decreased lifespan in some cases, possibly due to the signaling function some of these molecules have–. With doxorubicin treatment, similar objections have been suggested. Firstly, free radicals do not form immediately after treatment. Antioxidant enzymes could not prevent doxorubicin-induced DNA damage, indicating another mechanism. Secondly, clinical trials showed that antioxidants could not prevent the accelerated aging phenotype in DCT patients,,, while in animals upregulation of antioxidant enzymes has a beneficial effect,. Lastly, it remains unclear whether antioxidant therapy influences the cancer efficacy of doxorubicin, rendering it impractical for clinical use.

Calcium flux

Calcium regulates contraction of cardiomyocytes. During an action potential, Ryanodine Receptor 2 (RyR2) releases calcium from the sarcoplasmic reticulum (SR). This calcium spike activates the sarcomeres, and the cell shortens. Subsequently, SR Ca2+-stimulated ATPase (SERCA) pumps calcium back into the SR and the cell relaxes. In both aged and doxorubicin-treated mice the amount of phosphorylated troponin I increased, indicating that relaxation of the cardiomyocyte is impaired. In human aged cells, calcium concentration remains high for longer and relaxation is slower,. RyR2 and SERCA are responsible for these changes. The likelihood of RyR2 being in its open conformation increases with age (leaking), while it is activated by doxorubicin treatment–. SERCA activity has been shown to be decreased both with age and doxorubicin treatment,. This is partially due to decreased phosphorylation of phospholamban, an inhibitor of SERCA, and decreased ATP content.

Involvement of the immune system in aging and DCT

The immune system’s response to aging and DCT illustrates a complex interplay, characterized by the secretion of chemokines, cytokines, and growth factors, collectively forming the senescence-associated secretory phenotype (SASP). During aging, the upregulation of pro-inflammatory cytokines such as IL-6 and TNF-α, alongside chemokines like CCL2 and CXCL12, establishes a chronic inflammatory state within the heart,. This inflammatory environment induces cellular stress and fosters cardiac cell senescence, contributing to the decline in cardiac function.

In the context of DCT, a similar pro-inflammatory response is demonstrated, marked by the elevation of SASP factors. Studies have demonstrated that expression of cytokines such as IFN-γ, CCL27, and MIF is increased in patients undergoing doxorubicin treatment, linking them to the DCT process,–. This response is part of a broader systemic reaction, where the immune system attempts to mitigate the damage caused by the chemotherapeutic agent but instead contributes to the deterioration of cardiac tissue.

The role of growth factors within the SASP, such as TGF-β and PDGF, is critically involved in cardiac remodeling and fibrosis, processes that are prominent in both aging and DCT,. The presence of increased SASP production both in DCT and aging underscores the concept of an accelerated aging phenotype in DCT. This similarity in cytokine, chemokine, and growth factor expression and activity between aging and DCT suggests shared mechanisms, offering potential therapeutic targets or biomarkers,. Modulating the inflammatory response could present new strategies for mitigating the effects of both aging and DCT. For example, Zymosan A has been shown to improve cardiac healing and ameliorate doxorubicin-induced ventricular remodeling. This was achieved by a heightened cardiac inflammatory response, leading to enhanced repair in DCT mice–.

Senescence as a biomarker

Senescence could be used as a biomarker for predicting outcomes of DCT. Senescent cells secrete SASP factors, which can be detected in the blood. Several SASP factors have already been linked to worse prognosis in cardiovascular disease. Examples are IGFBP7,, interleukin-6 (IL-6),, and GDF-15,. Patients with chronic heart failure (BIOSTAT-CHF) with elevated levels of IGFBP7 showed a 44% (HR = 1.44 [CI 1.23–1.70], p < 0.001) increase in combined adverse endpoints. Increased IL-6 levels have also been reported in women who experienced cardiovascular events versus healthy women (1.65 versus 1.30 pg/ml, p = 0.003). GDF-15 is upregulated upon doxorubicin treatment and has been proposed as a cardiomyocyte-specific SASP factor. Higher levels of GDF-15 in the blood predict worse outcome: A significant correlation between GDF-15 and death (HR = 1.66 [SD 1.07–1.26] p < 0.001), heart failure (HR = 1.52 [SD 1.29–1.78], p < 0.001), and major cardiovascular events (HR = 1.26 [SD 1.14–1.41], p < 0.001) was found. However, large trials investigating SASP levels in the blood of patients treated with doxorubicin have not been conducted.

Senotherapeutics

Research has indicated that a promising approach to protect the heart against DCT involves the removal of senescent cells. By employing a transgenic model that enables the targeted elimination of p16-expressing cells, cardiac function was successfully restored. Consequently, two classes of drugs, known as senolytics and senomorphics, hold potential for both DCT treatment and the broader context of combating aging. Senolytics cause cell death of senescent cells specifically, while senomorphics prevent cells from becoming senescent by modulating SASP expression.

Senescent cells can resist apoptosis by upregulating anti-apoptotic genes such as Bcl-2. Senolytics target this phenotype to remove senescent cells from a tissue. This has beneficial effects on health-span in general. The first senolytic compounds to be discovered, were dasatinib and quercetin. When administered together, heart function in 24-month-old mice was improved, but they were never tested in DCT. Another compound that was designed to inhibit anti-apoptotic proteins is navitoclax. Navitoclax is being investigated in clinical trials as an anti-tumor drug for multiple cancer types and the results are promising. It has also been shown to improve cardiac function in doxorubicin-treated mice. FOXO4-DRI is a senolytic that was designed to disrupt p53-FOXO4 complexes, causing p53 to initiate apoptosis instead of senescence. This peptide can protect against doxorubicin-induced liver damage, but its effect on DCT has not been investigated. Fisetin is a bioflavonoid that can be found in many types of plants and fruits, including strawberries and apples. It has senolytic properties and increases healthspan. In doxorubicin-treated rats, it has a beneficial effect on heart function.

Senomorphics include a wide range of compounds, many of them natural products. They affect the cells in multiple ways, making their exact mechanism of action difficult to establish,. Several have been shown to be effective against DCT in animal models: resveratrol, metformin, PJ34, and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). For example, rats that were co-treated with doxorubicin and AICAR had a preserved ejection fraction after six weeks. Human data on the efficacy of these compounds in DCT is scarce and mostly based on in vitro research–. The effect of resveratrol in combination with other compounds on cardiovascular disease has been investigated. The results of these trials were marginally positive, but the effect of resveratrol alone was not assessed. Besides, conventional heart failure therapies have limited efficacy in DCT patients–. Therefore, the effect of resveratrol on DCT could differ from what is observed in other cardiovascular etiologies. This was supported by a recent study from our lab. iPSC-CM-based dynamic engineered heart tissues were subjected to four clinically relevant doses of doxorubicin over the course of four weeks and co-treated either with resveratrol or AICAR. Neither resveratrol nor AICAR was able to improve the phenotype induced by doxorubicin. It was suggested that prevention of senescence resulted in apoptosis and ultimately in worsening of the function in the case of the AICAR treated tissues. This indicates that treatment with senomorphics in DCT could be detrimental and that preclinical experiments using animals might not be accurate predictors of the outcome in humans.

Future perspectives

Further research into the underlying mechanisms linking cardiovascular disease and cancer is one of the Gaps in Evidence highlighted by the ESC 2022 Guidelines on Cardio-Oncology. In this review, we have discussed the evidence of an accelerated aging phenotype in the hearts of DCT patients. A comparison was made between the healthy aged heart and the doxorubicin-treated heart. On a macroscopic level, there were some similarities, such as hypertrophy and fibrosis. Most resemblances were found at cell level, where we described an increased number of mutations, upregulation of senescence markers, shorter telomeres, declining histone levels, decreased DNA methylation, decreased Sirtuin activity, less availability of substrates for epigenetic modifications, decreased energy production, increased mtDNA damage, increased ROS production, and dysfunctional calcium handling. Doxorubicin was in all instances able to initiate mechanisms that would otherwise happen gradually with time, suggesting doxorubicin treatment leads to an accelerated aging phenotype. Although this review discusses most well-known processes involved in both aging and doxorubicin treatment, not all are elaborately explained. Mechanisms for which less evidence exists, or for which evidence is controversial were omitted, for example autophagy,,, and inflammation,.

More research on the involvement of senescence in DCT is merited. However, special care should be taken in selecting the experimental model. Rats and mice are much more resilient to doxorubicin than humans, meaning that higher dosages of doxorubicin have to be administered. It is known that different concentrations of doxorubicin activate separate mechanisms, suggesting that DCT in mice and rats might have a different origin than in humans. Besides that, we have seen that the effect of senolytics is positive in mice and rats with DCT, while it worsens function in human 3D models. Parallel to this, it has been observed that antioxidant molecules have a beneficial effect on experimental animal models of DCT and not in clinical trials. This discrepancy could be due a difference in underlying mechanism, or to higher regeneration rates of cardiomyocytes in mice (1.3–4%) compared to humans (0.3–1%).

All this knowledge is instrumental in developing cardioprotective strategies. Numerous avenues are being explored to protect the heart from DCT, including the use of dexrazoxane, honokiol, and curcumin, many of which target either mitochondrial function or inflammation. Another cardioprotective strategy involves co-treating with doxorubicin and SGLT-2 inhibitors. A retrospective study including 32 patients who had received doxorubicin and SGLT-2 inhibitors showed no development of DCT. In a pre-clinical model of DCT, empagliflozin showed decreased fibrosis, decreased inflammation, decreased oxidative stress, decreased lipid peroxidation, and increased mitochondrial biogenesis and left ventricular function.

All this evidence taken together suggests that the heart undergoes an accelerated aging phenotype after doxorubicin exposure. Since many differences between the human heart and the heart of animals are observed, this should be taken into account when designing new experiments.

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    Speth P, Linssen P, Boezeman J, Wessels H, Haanen C. Cellular and plasma adriamycin concentrations in long-term infusion therapy of leukemia patients. Cancer Chemother. Pharmacol. 1987;20:305-310.

    Not in our library10.1007/bf00262581

  25. 25.

    Muller C, et al. Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia: comparison of bolus administration and continuous infusion. Cancer Chemother. Pharmacol. 1993;32:379-384.

    Not in our library10.1007/bf00735923

  26. 26.

    Greene RF, Collins JM, Jenkins JF, Speyer JL, Myers CE. Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols. Cancer Res. 1983;43:3417-3421.

    Not in our library

  27. 27.

    Gunvén P, Theve NO, Peterson C. Serum and tissue concentrations of doxorubicin after IV administration of doxorubicin or doxorubicin-DNA complex to patients with gastrointestinal cancer. Cancer Chemother. Pharmacol. 1986;17:153-156.

    Not in our library10.1007/bf00306745

  28. 28.

    Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J. Clin. Oncol. 1988;6:1321-1327.

    Not in our library10.1200/jco.1988.6.8.1321

  29. 29.

    Sturgeon K, et al. Concomitant low-dose doxorubicin treatment and exercise. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014;307:R685-R692.

    Not in our library10.1152/ajpregu.00082.2014

  30. 30.
    Liquid Chromatography–Tandem Mass Spectrometry for the Simultaneous Determination of Doxorubicin and its Metabolites Doxorubicinol, Doxorubicinone, Doxorubicinolone, and 7-Deoxydoxorubicinone in Mouse Plasma · 2020
    Not checked
  31. 31.

    Shi J, Guo Y, Cheng L, Song F, Shu X. Early change in left atrial function in patients treated with anthracyclines assessed by real-time three-dimensional echocardiography. Sci. Rep. 2016;6:25512.

    Not in our library10.1038/srep25512

  32. 32.

    Gerstenblith G, et al. Echocardiographic assessment of a normal adult aging population. Circulation. 1977;56:273-278.

    Not in our library10.1161/01.cir.56.2.273

  33. 33.

    Cheng S, et al. Age-related left ventricular remodeling and associated risk for cardiovascular outcomes the multi-ethnic study of atherosclerosis. Circ. Cardiovasc. Imaging. 2009;2:191-198.

    Not in our library10.1161/circimaging.108.819938

  34. 34.

    van Grootel RWJ, et al. In-depth echocardiographic analysis of left atrial function in healthy adults using speckle tracking echocardiography and volumetric analysis. Echocardiography. 2018;35:1956-1965.

    Not in our library10.1111/echo.14174

  35. 35.

    Hausdorf G, et al. Long term doxorubicin cardiotoxicity in childhood: non-invasive evaluation of the contractile state and diastolic filling. Heart. 1988;60:309-315.

    Not in our library10.1136/hrt.60.4.309

  36. 36.

    Yaylali, Y. T., Saricopur, A., Yurtdas, M., Senol, H. & Gokoz-Dogu, G. Atrial function in patients with breast cancer after treatment with Anthracyclines. Arq. Bras. Cardiol.10.5935/abc.20160146 (2016).

    Not in our library10.5935/abc.20160146

  37. 37.

    Roberts JD, et al. Epigenetic age and the risk of incident atrial fibrillation. Circulation. 2021;144:1899-1911.

    Not in our library10.1161/circulationaha.121.056456

  38. 38.

    Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32:302-314.

    Not in our library10.1002/1097-0142(197308)32:2<302::aid-cncr2820320205>3.0.co;2-2

  39. 39.

    Kilickap S, et al. Early and late arrhythmogenic effects of doxorubicin. South Med. J. 2007;100:262-265.

    Not in our library10.1097/01.smj.0000257382.89910.fe

  40. 40.

    Go AS, et al. Prevalence of diagnosed atrial fibrillation in adults. JAMA. 2001;285:2370.

    Not in our library10.1001/jama.285.18.2370

  41. 41.

    Nattel S. Aging and protein kinase activation is it the missing link between age and atrial fibrillation? Circ. Res. 2018;122:799-801.

    Not in our library10.1161/circresaha.118.312786

  42. 42.

    Rabkin SW. Aging effects on QT interval: implications for cardiac safety of antipsychotic drugs. J. Geriatr. Cardiol. 2014;11:20-25.

    Not in our library10.3969/j.issn.1671-5411.2014.01.005

  43. 43.

    Rabkin SW, Cheng XBJ, Thompson DJS. Detailed analysis of the impact of age on the QT interval. J. Geriatr. Cardiol. 2016;13:740-748.

    Not in our library10.11909/j.issn.1671-5411.2016.09.013

  44. 44.

    Acun A, Nguyen TD, Zorlutuna P. In vitro aged, hiPSC-origin engineered heart tissue models with age-dependent functional deterioration to study myocardial infarction. Acta Biomater. 2019;94:372-391.

    Not in our library10.1016/j.actbio.2019.05.064

  45. 45.
    Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence · 2019
    No notice
  46. 46.

    Lieber SC, et al. Aging increases stiffness of cardiac myocytes measured by atomic force microscopy nanoindentation. Am. J. Physiol.-Heart Circ. Physiol. 2004;287:H645-H651.

    Not in our library10.1152/ajpheart.00564.2003

  47. 47.

    Hua Y, et al. Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res. Cardiol. 2011;106:1173-1191.

    Not in our library10.1007/s00395-011-0222-8

  48. 48.

    Dai DF, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 2009;119:2789-2797.

    Not in our library10.1161/circulationaha.108.822403

  49. 49.

    Häseli S, Deubel S, Jung T, Grune T, Ott C. Cardiomyocyte contractility and autophagy in a premature senescence model of cardiac aging. Oxid. Med. Cell. Longev. 2020;2020:1-14.

    Not in our library10.1155/2020/8141307

  50. 50.
    Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling · 2016
    No notice
  51. 51.

    Du Q, Zhu B, Zhai Q, Yu B. Sirt3 attenuates doxorubicin-induced cardiac hypertrophy and mitochondrial dysfunction via suppression of Bnip3. Am. J. Transl. Res. 2017;9:3360-3373.

    Not in our library

  52. 52.

    Shi J, Surma M, Wei L. Disruption of ROCK1 gene restores autophagic flux and mitigates doxorubicin-induced cardiotoxicity. Oncotarget. 2018;9:12995-13008.

    Not in our library10.18632/oncotarget.24457

  53. 53.

    Burridge PW, et al. Human induced pluripotent stem cell–derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 2016;22:547-556.

    Not in our library10.1038/nm.4087

  54. 54.

    Adamcova M, Skarkova V, Seifertova J, Rudolf E. Cardiac troponins are among targets of doxorubicin-induced cardiotoxicity in hiPCS-CMs. Int. J. Mol. Sci. 2019;20:2638.

    Not in our library10.3390/ijms20112638

  55. 55.

    Hees PS, Fleg JL, Lakatta EG, Shapiro EP. Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. Am. J. Cardiol. 2002;90:1231-1236.

    Not in our library10.1016/s0002-9149(02)02840-0

  56. 56.

    Tan TC, et al. Time trends of left ventricular ejection fraction and myocardial deformation indices in a cohort of women with breast cancer treated with Anthracyclines, Taxanes, and Trastuzumab. J. Am. Soc. Echocardiogr. 2015;28:509-514.

    Not in our library10.1016/j.echo.2015.02.001

  57. 57.

    Kakimoto Y, et al. Myocardial lipofuscin accumulation in ageing and sudden cardiac death. Sci. Rep. 2019;9:3304.

    Not in our library10.1038/s41598-019-40250-0

  58. 58.

    Kim YY, et al. Anti-aging effects of vitamin C on human pluripotent stem cell-derived cardiomyocytes. Age. 2012;35:1545-1557.

    Not in our library10.1007/s11357-012-9457-z

  59. 59.
    Aged‐senescent cells contribute to impaired heart regeneration · 2019
    No notice
  60. 60.

    Debessa, G., Beatriz, L. & Maifrino, M. Age related changes of the collagen network of the human heart. 122, 1049–1058 (2001).

    Not in our library10.1016/s0047-6374(01)00238-x

  61. 61.
    Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts. · 2020
    Not checked
  62. 62.

    Tanaka R, et al. Reactive fibrosis precedes doxorubicin‐induced heart failure through sterile inflammation. ESC Heart Fail. 2020;7:588-603.

    Not in our library10.1002/ehf2.12616

  63. 63.

    Chan BYH, et al. MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling. Cardiovasc. Res. 2021;117:188-200.

    Not in our library10.1093/cvr/cvaa017

  64. 64.

    Demaria M, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 2017;7:165-176.

    Not in our library10.1158/2159-8290.cd-16-0241

  65. 65.
    Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments · 2020
    No notice
  66. 66.

    Hwang HJ, et al. Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer Lett. 2020;490:100-110.

    Not in our library10.1016/j.canlet.2020.06.019

  67. 67.

    De Angelis A, et al. Doxorubicin cardiotoxicity and target cells: a broader perspective. Cardio-Oncol. 2016;2:2.

    Not in our library10.1186/s40959-016-0012-4

  68. 68.

    Bailleul, A. M. et al. Evidence of proteins, chromosomes and chemical markers of DNA in exceptionally preserved dinosaur cartilage. Natl. Sci. Rev.10.1093/nsr/nwz206 (2020).

    Not in our library10.1093/nsr/nwz206

  69. 69.

    Ou H-L, Schumacher B. DNA damage responses and p53 in the aging process. Blood. 2018;131:488-495.

    Not in our library10.1182/blood-2017-07-746396

  70. 70.

    Agudelo D, Bourassa P, Bérubé G, Tajmir-Riahi HA. Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: structural features and biological implications. Int. J. Biol. Macromol. 2014;66:144-150.

    Not in our library10.1016/j.ijbiomac.2014.02.028

  71. 71.

    Chen NT, et al. Probing the dynamics of Doxorubicin-DNA intercalation during the initial activation of apoptosis by Fluorescence Lifetime Imaging Microscopy (FLIM). PLoS One. 2012;7:3-10.

    Not in our library10.1371/journal.pone.0044947

  72. 72.

    Skladanowski A, Konopa J. Interstrand DNA crosslinking induced by anthracyclines in tumour cells. Biochem. Pharmacol. 1994;47:2269-2278.

    Not in our library10.1016/0006-2952(94)90265-8

  73. 73.

    Vavrova A, et al. Catalytic inhibitors of Topoisomerase II differently modulate the toxicity of anthracyclines in cardiac and cancer cells. PLoS One. 2013;8:e76676.

    Not in our library10.1371/journal.pone.0076676

  74. 74.

    Yi LL, et al. Topoisomerase IIβ-mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007;67:8839-8846.

    Not in our library10.1158/0008-5472.can-07-1649

  75. 75.

    Zhang S, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 2012;18:1639-1642.

    Not in our library10.1038/nm.2919

  76. 76.

    Yang F, Teves SS, Kemp CJ, Henikoff S. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim. Biophys. Acta. 2014;1845:84-89.

    Not in our library10.1016/j.bbcan.2013.12.002

  77. 77.

    Yang F, Kemp CJ, Henikoff S. Doxorubicin enhances nucleosome turnover around promoters. Curr. Biol. 2013;23:782-787.

    Not in our library10.1016/j.cub.2013.03.043

  78. 78.

    Congras A, et al. Doxorubicin-induced loss of DNA topoisomerase II and DNMT1- dependent suppression of MiR-125b induces chemoresistance in ALK-positive cells. Oncotarget. 2018;9:14539-14551.

    Not in our library10.18632/oncotarget.24465

  79. 79.

    Capranico G, Kohn KW, Pommier Y. Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin. Nucleic Acids Res. 1990;18:6611-6619.

    Not in our library10.1093/nar/18.22.6611

  80. 80.
    Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms · 2014
    No notice
  81. 81.

    Smith, J., Tho, L. M., Xu, N. & Gillespie, D. A. The ATM–Chk2 and ATR–Chk1 pathways in DNA damage signaling and cancer. Adv. Cancer Res. 108, 73–112 (Elsevier Inc., 2010).

    Not in our library10.1016/b978-0-12-380888-2.00003-0

  82. 82.

    Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018;25:104-113.

    Not in our library10.1038/cdd.2017.169

  83. 83.

    Baar MP, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017;169:132-147.e16.

    Not in our library10.1016/j.cell.2017.02.031

  84. 84.

    Thornton TM, Rincon M. Non-classical p38 map kinase functions: cell cycle checkpoints and survival. Int. J. Biol. Sci. 2009;5:44-52.

    Not in our library10.7150/ijbs.5.44

  85. 85.

    Ruan Y, et al. SIRT1 suppresses Doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways. Cell. Physiol. Biochem. 2015;35:1116-1124.

    Not in our library10.1159/000373937

  86. 86.

    Kajstura J, et al. The Telomere–Telomerase axis and the heart. Antioxid. Redox Signal. 2006;8:2125-2141.

    Not in our library10.1089/ars.2006.8.2125

  87. 87.

    Terai M, et al. Association of telomere shortening in myocardium with heart weight gain and cause of death. Sci. Rep. 2013;3:2401.

    Not in our library10.1038/srep02401

  88. 88.

    Hewitt G, et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 2012;3:1-9.

    Not in our library10.1038/ncomms1708

  89. 89.

    Spallarossa, P. et al. Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. Am. J. Physiol. Heart Circ. Physiol. 2169–2181 10.1152/ajpheart.00068.2009 (2009).

    Not in our library10.1152/ajpheart.00068.2009

  90. 90.

    Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 2016;17:487-500.

    Not in our library10.1038/nrg.2016.59

  91. 91.

    Cakouros D, Gronthos S. Epigenetic regulation of bone marrow stem cell aging: revealing epigenetic signatures associated with hematopoietic and mesenchymal stem cell aging. Aging Dis. 2019;10:174.

    Not in our library10.14336/ad.2017.1213

  92. 92.

    Pang B, et al. Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat. Commun. 2013;4:1908.

    Not in our library10.1038/ncomms2921

  93. 93.
    DNA methylation and healthy human aging · 2015
    No notice
  94. 94.

    Sakai K, et al. Effects of doxorubicin on sperm DNA methylation in mouse models of testicular toxicity. Biochem. Biophys. Res. Commun. 2018;498:674-679.

    Not in our library10.1016/j.bbrc.2018.03.044

  95. 95.

    Ferreira A, et al. Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity. Toxicology. 2017;390:63-73.

    Not in our library10.1016/j.tox.2017.08.011

  96. 96.

    Nordgren KKS, Hampton M, Wallace KB. Editor’s highlight: the altered DNA Methylome of chronic doxorubicin exposure in sprague dawley rats. Toxico. Sci. 2017;159:470-479.

    Not in our library10.1093/toxsci/kfx150

  97. 97.
    DNA methylation age of human tissues and cell types · 2013
    Corrected
  98. 98.
    An epigenetic biomarker of aging for lifespan and healthspan · 2018
    No notice
  99. 99.

    Chaudhari U, et al. Metabolite signatures of doxorubicin induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes. Amino Acids. 2017;49:1955-1963.

    Not in our library10.1007/s00726-017-2419-0

  100. 100.

    Booth LN, Brunet A. The aging epigenome. Mol. Cell. 2016;62:728-744.

    Not in our library10.1016/j.molcel.2016.05.013

  101. 101.

    Shimazu T, Hirschey MD, Huang J-Y, Ho LTY, Verdin E. Acetate metabolism and aging: an emerging connection. Mech. Ageing Dev. 2010;131:511-516.

    Not in our library10.1016/j.mad.2010.05.001

  102. 102.

    De Angelis A, et al. SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells. Int. J. Cardiol. 2015;189:30-44.

    Not in our library10.1016/j.ijcard.2015.03.438

  103. 103.

    Dolinsky VW. The role of sirtuins in mitochondrial function and doxorubicin-induced cardiac dysfunction. Biol. Chem. 2017;398:955-974.

    Not in our library10.1515/hsz-2016-0316

  104. 104.
    Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice · 2017
    No notice
  105. 105.

    Tang H, et al. Doxorubicin-induced cardiomyocyte apoptosis: Role of mitofusin 2. Int. J. Biochem. Cell Biol. 2017;88:55-59.

    Not in our library10.1016/j.biocel.2017.05.006

  106. 106.

    Lesnefsky EJ, Chen Q, Hoppel CL. Mitochondrial metabolism in aging heart. Circ. Res. 2016;118:1593-1611.

    Not in our library10.1161/circresaha.116.307505

  107. 107.

    El’darov ChM, Vays VB, Vangeli IM, Kolosova NG, Bakeeva LE. Morphometric examination of mitochondrial ultrastructure in aging cardiomyocytes. Biochemistry. 2015;80:604-609.

    Not in our library10.1134/s0006297915050132

  108. 108.
    Changes of mitochondrial ultrastructure and function during ageing in mice and Drosophila · 2017
    No notice
  109. 109.

    Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 2014;171:2029-2050.

    Not in our library10.1111/bph.12461

  110. 110.

    Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E. Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin. FEBS Lett. 1997;406:136-138.

    Not in our library10.1016/s0014-5793(97)00264-0

  111. 111.

    Ichikawa Y, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Investig. 2014;124:617-630.

    Not in our library10.1172/jci72931

  112. 112.

    Anderson AB, Arriaga EA. Subcellular metabolite profiles of the parent CCRF-CEM and the derived CEM/C2 cell lines after treatment with doxorubicin. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2004;808:295-302.

    Not in our library10.1016/j.jchromb.2004.05.017

  113. 113.

    Goormaghtigh E, Chatelain P, Caspers J, Ruysschaert JM. Evidence of a complex between adriamycin derivatives and cardiolipin: possible role in cardiotoxicity. Biochem. Pharmacol. 1980;29:3003-3010.

    Not in our library10.1016/0006-2952(80)90050-7

  114. 114.

    Liu L, et al. Over-expression of heat shock protein 27 attenuates doxorubicin-induced cardiac dysfunction in mice. Eur. J. Heart Fail. 2007;9:762-769.

    Not in our library10.1016/j.ejheart.2007.03.007

  115. 115.

    Wan Q, et al. miR-499-5p attenuates mitochondrial fission and cell Apoptosis via p21 in Doxorubicin Cardiotoxicity. Front. Genet. 2019;9:734.

    Not in our library10.3389/fgene.2018.00734

  116. 116.

    Carvalho RA, et al. Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy. Toxicology. 2010;270:92-98.

    Not in our library10.1016/j.tox.2010.01.019

  117. 117.

    Carvalho FS, et al. Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 2013;34:106-135.

    Not in our library10.1002/med.21280

  118. 118.
    Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte · 2020
    Not checked
  119. 119.

    Martín-Fernández B, Gredilla R. Mitochondria and oxidative stress in heart aging. Age. 2016;38:225-238.

    Not in our library10.1007/s11357-016-9933-y

  120. 120.
    Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes · 2016
    No notice
  121. 121.

    Jeyaseelan R, Poizat C, Wu H, Kedes L. Molecular mechanisms of Doxorubicin-induced cardiomyopathy. J. Biol. Chem. 1997;272:5828-5832.

    Not in our library10.1074/jbc.272.9.5828

  122. 122.

    Pointon AV, et al. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS One. 2010;5:1-17.

    Not in our library10.1371/journal.pone.0012733

  123. 123.

    Zhang Y, et al. Doxorubicin induces sarcoplasmic reticulum calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats. Cell Biochem. Biophys. 2014;70:1791-1798.

    Not in our library10.1007/s12013-014-0130-2

  124. 124.

    Bordoni A, Biagi P, Hrelia S. The impairment of essential fatty acid metabolism as a key factor in doxorubicin-induced damage in cultured rat cardiomyocytes. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 1999;1440:100-106.

    Not in our library10.1016/s1388-1981(99)00113-4

  125. 125.

    Guan R, et al. Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts. Eur. Respir. J. 2022;60:2102307.

    Not in our library10.1183/13993003.02307-2021

  126. 126.

    Trifunovic A, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417-423.

    Not in our library10.1038/nature02517

  127. 127.

    Sangomla S, Saifi MA, Khurana A, Godugu C. Nanoceria ameliorates doxorubicin induced cardiotoxicity: possible mitigation via reduction of oxidative stress and inflammation. J. Trace Elements Med. Biol. 2018;47:53-62.

    Not in our library10.1016/j.jtemb.2018.01.016

  128. 128.

    Tang WHW, Mullens W. Cardiorenal syndrome in decompensated heart failure. Heart. 2010;96:255-260.

    Not in our library10.1136/hrt.2009.166256

  129. 129.

    Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28:436-453.

    Not in our library10.1016/j.tcb.2018.02.001

  130. 130.

    Berthiaume JM, Wallace KB. Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol. Toxicol. 2007;23:15-25.

    Not in our library10.1007/s10565-006-0140-y

  131. 131.

    Bachur NR, Gee MV, Friedman RD. Nuclear catalyzed antibiotic free radical formation. Cancer Res. 1982;42:1078-1081.

    Not in our library

  132. 132.

    Zhu H, et al. Doxorubicin redox biology: redox cycling, topoisomerase inhibition, and oxidative stress. React. Oxyg. Species. 2016;1:189-198.

    Not in our library10.20455/ros.2016.835

  133. 133.
    Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree? · 2020
    Not checked
  134. 134.

    Treuting PM, et al. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J. Gerontol. A Biol. Sci. Med. Sci. 2008;63:813-822.

    Not in our library10.1093/gerona/63.8.813

  135. 135.
    Mitochondria and PGC-1α in Aging and Age-Associated Diseases · 2011
    No notice
  136. 136.

    Cesselli D, et al. Cardiac cell senescence and redox signaling. Front. Cardiovasc. Med. 2017;4:38.

    Not in our library10.3389/fcvm.2017.00038

  137. 137.

    Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. JAMA. 2007;297:842.

    Not in our library10.1001/jama.297.8.842

  138. 138.

    Dresdale AR, et al. Prospective randomized study of the role of N-acetyl cysteine in reversing doxorubicin-induced cardiomyopathy. Am. J. Clin. Oncol. 1982;5:657-664.

    Not in our library10.1097/00000421-198212000-00015

  139. 139.

    Singh K, Bhori M, Kasu YA, Bhat G, Marar T. Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity – Exploring the armoury of obscurity. Saudi Pharm. J. 2018;26:177-190.

    Not in our library10.1016/j.jsps.2017.12.013

  140. 140.

    Vincent DT, Ibrahim YF, Espey MG, Suzuki YJ. The role of antioxidants in the era of cardio-oncology. Cancer Chemother. Pharmacol. 2013;72:1157-1168.

    Not in our library10.1007/s00280-013-2260-4

  141. 141.

    Herraiz-Martínez A, et al. Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes. Cardiovasc. Res. 2015;106:76-86.

    Not in our library10.1093/cvr/cvv046

  142. 142.

    Janczewski AM, Lakatta EG. Modulation of sarcoplasmic reticulum Ca2+ cycling in systolic and diastolic heart failure associated with aging. Heart Fail. Rev. 2010;15:431-445.

    Not in our library10.1007/s10741-010-9167-5

  143. 143.

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