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Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

Ana Laura V. Alves, Izabela N. F. Gomes, Adriana C. Carloni and 5 more

Stem Cell Research & Therapy · 2021 · Review · CC BY

Abstract

Glioblastoma (GBM) is the highest-grade form of glioma, as well as one of the most aggressive types of cancer, exhibiting rapid cellular growth and highly invasive behavior. Despite significant advances in diagnosis and therapy in recent decades, the outcomes for high-grade gliomas (WHO grades III-IV) remain unfavorable, with a median overall survival time of 15–18 months. The concept of cancer stem cells (CSCs) has emerged and provided new insight into GBM resistance and management. CSCs can self-renew and initiate tumor growth and are also responsible for tumor cell heterogeneity and the induction of systemic immunosuppression. The idea that GBM resistance could be dependent on innate differences in the sensitivity of clonogenic glial stem cells (GSCs) to chemotherapeutic drugs/radiation prompted the scientific community to rethink the understanding of GBM growth and therapies directed at eliminating these cells or modulating their stemness. This review aims to describe major intrinsic and extrinsic mechanisms that mediate chemoradioresistant GSCs and therapies based on antineoplastic agents from natural sources, derivatives, and synthetics used alone or in synergistic combination with conventional treatment. We will also address ongoing clinical trials focused on these promising targets. Although the development of effective therapy for GBM remains a major challenge in molecular oncology, GSC knowledge can offer new directions for a promising future.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Gliomas are the most frequent primary brain tumors in adults, accounting for more than 80% of all malignant cerebral neoplasms. Among these tumors, glioblastoma (GBM) is the most common primary intracranial tumor with a very poor prognosis (WHO grade IV), representing 57.3% of all gliomas. These tumors can be divided into IDH wild type, clinically defined as primary or de novo glioblastoma, which corresponds to approximately 90% of GBM cases and generally occurs in patients aged 62 or older, and IDH mutant, corresponding to secondary glioblastoma (approximately 10% of cases) that progressively develops from low-grade astrocytoma and frequently manifests in patients aged 40–50 years old (Fig. 1). Currently, the most frequent molecular alterations associated with primary GBM are epidermal growth factor (EGFR) amplification or mutation, loss of heterozygosity (LOH) of chromosome 10q at the phosphatase and tensin homolog (PTEN) locus, and TERT gene promoter mutation (Fig. 1). Moreover, combined deletion of the complete 1p and 19q after unbalanced translocation between chromosomes 1 and 19 resulting in the 1p19q codeletion, homozygous deletion of CDKN2A-p16, loss of tumor suppressor genes such as TP53 and ATRX, and IDH1/2 gene mutations are common molecular alterations found in secondary GBM (Fig. 1). The amplification of the EGFR gene affects the development and progression of gliomas, conferring more aggressive properties, and can be used as a therapeutic target (Fig. 1). Recent studies showed that the TERT promoter mutation essentially accounted for primary GBM and was associated with aggressiveness and poor survival (Fig. 1). Although the presence of the 1p19q codeletion is associated with higher survival, CDKN2A-p16 deletion was associated with poor prognosis. The association of TP53 mutation in GBM and ATRX mutation has not been consistent. So far, it is known that both can co-occur. Importantly, IDH mutations are well-established markers of better prognosis. Genomic studies have also described five molecular subclasses (mesenchymal, classical (or proliferative), proneural, neural, and G-CIMP). Despite improvements in the knowledge and molecular characterization of glioblastomas, no significant difference in patient survival has been observed between primary and secondary glioblastomas, with both showing a mean survival of 12 to 15 months and a high frequency of tumor relapse.

2The gold standard treatment for GBM patients is surgical resection combined with radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide (TMZ). Although some molecular features have been proposed as predictive biomarkers of the treatment response to alkylating agents, such as the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter, the clinical utility of these markers is minimal. Some reasons proposed for this resistance may include the diffuse infiltrative nature to the surrounding brain, which hinders total resection; the high heterogeneity of GBM, involving distinct molecular pathways; and, more recently, the presence of stem cell-like tumorigenic features, including inducing angiogenesis, uncontrolled cellular proliferation, resisting cell death, and genome instability and mutation.

3Evidence of small populations of tumor cells that are similar to stem cells, known as cancer stem cells (CSCs) or tumor-initiating cells, has been known as a cause of tumor initiation and development since the nineteenth century and was first described in hematologic malignancies in 1994.

4The first evidence of brain stem cells was shown by Ignatova et al. and later supported by several other groups. In glioblastoma, glioblastoma stem cells (GSCs) were first identified by Singh et al. as a population of cells capable of initiating tumor growth in vivo. The first accepted GSC surface marker was CD133. This marker allows the subdivision of stem cells into two groups: CD133-positive cells (CD133+), or cancer stem cells, and CD133-negative cells (CD133−), or non-cancer stem cells. CD133 expression also enables the characterization of cell self-renewal capacity, as there is a decrease in the expression of this surface marker during cell differentiation. Another critical feature of CD133+ cells is the capacity to generate neurospheres in vitro and induce brain tumor formation in in vivo models. Other markers have also been associated with GSCs that together classify a signature of these cells. According to Dirks and coworkers, CD15 and CD133 are the most useful surface markers of GSCs reported to date and stand out compared to other markers. The presence of dual CD133+/Ki-67+ cells and associated Nestin or HOX genes is an adverse prognostic factor for GBM progression. Another marker highly expressed in GSCs is the CXCR4 chemokine receptor (CD184), which is associated with CD133+ cells and increased expression of hypoxia-inducible factor (HIF-1-α). The same importance should be assigned to the MUSASHI-1 protein, a regulator of translation and cellular fate. Other markers, including the cell-surface glycoprotein CD44; the cell-surface gangliosides A2B5, CD90, and SOX2; and ALDH1, L1CAM, KLF4, SALL4, and GFAP, have also been also used for the identification of GSCs. However, the specificity of the surface marker CD133 remains unclear, with groups reporting the identification of GSCs that are CD133 negative. Therefore, it is also noteworthy that although CD133 and CD44 persist on genetically diverse clones, the presence of more primitive markers, such as OCT-4, SALL4, and NANOG, among others, needs to be better defined and may be key to developing novel and effective treatments for GBMs. The main biomarkers are summarized in Fig. 2.

5Therefore, the promising GSC hypothesis offers new insight into cancer diagnosis and adds complexity in the management of brain tumors. The concept that GBM resistance could be dependent on innate differences in the sensitivity of clonogenic GSCs to chemotherapeutic drugs/radiation stimulated the scientific community to rethink the understanding of GBM growth and therapies designed to be directed at eliminating these cells or modulating their stemness. So far, the research strategies involve the development of drugs that target cancer stemness, directly or indirectly, in order to target multiple molecules, either alone or in combination.

6This review aims to report intrinsic and extrinsic mechanisms that mediate chemoradioresistance in GSCs and therapies based on antitumor agents from natural sources, derivatives, and synthetics used alone or in synergistic combinations with conventional treatments. We will also summarize ongoing clinical trials focused on these promising targets. Although the development of effective therapies for GBM remains a major challenge in molecular oncology, GSC knowledge can offer new directions for a promising future.

Role of repair mechanism in mediating radioresistance

7Ionizing radiation (IR) from radiotherapy induces different types of DNA damage, especially DNA double-strand breaks (DSBs). Depending on the type of injury caused, DNA repair mechanisms and DNA damage checkpoints can be triggered, allowing cells to repair DNA damage and proliferate again. The cellular response to DNA damage has been considered as one of the leading survival mechanisms of tumor cells after radiotherapy.

8Preclinical evidence demonstrates that many of these protection mechanisms are activated in CSC populations, possibly resulting in treatment resistance. Bao et al. showed that CD133+ cell subpopulations are resistant to IR due to a more efficient repair system (phosphorylation of CHK1, CHK2, and H2AX form γ-H2AX foci) than the bulk of tumor cells and undergo apoptosis less frequently. Moreover, an increase in CD133+ cells was also evidenced in clinical samples from recurrent tumors after high-dose radiotherapy treatment. Among other DNA repair-related genes, RAD51 overexpression is observed in GSCs, and BRCA1 and BRCA2 showed upregulation in glioblastoma cell lines, which led to reduced DNA damage after irradiation. The activation of ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) also mediates radioresistance. In addition, other authors have reported that, in vitro, CD133+ primary cells are more radiosensitive than established glioma cell lines, with a reduced capacity to repair DNA double-strand breaks and an intact G2 checkpoint but no intra-S-phase checkpoint. Therefore, the applicability of CD133+ GBM as a model of radioresistance is still unclear. These data highlight the heterogeneity of the in vitro radiosensitivity that exists among primary cell lines and reveal that radioresistance may be independent of the intrinsic GSC characteristics.

Role of microenvironment in radioresistance

9One parameter that may influence radioresponse is the tumor microenvironment. Tumors are comprised of multiple components other than tumor cells (endothelial cells and multiple infiltrating inflammatory and immune cells, together with the extracellular matrix, cytokines, nitric oxide, and oxygen levels) which are also exposed to radiation during therapy, and their crosstalk might influence tumor stem cells’ response to radiation. The critical role of the microenvironment, along with GSCs, is supported directly and indirectly by the observation that GSCs reside in specific niches, distinct compartmentalized regions that present morphologically and functionally distinct functions (Fig. 2). The stem cell niche plays an indispensable role in homeostasis, regeneration, maintenance, and repair. There are at least three specialized tumor niches in GBM that include the vasculature as an integral regulatory component, including the perivascular tumor niche, vascular-invasive tumor niche, and hypoxic-necrotic tumor niche. These niches are dependent not only on normal cell components in the tumor microenvironment but also on the genetic and epigenetic profiles of GSCs. The different combinations of cell components and functional statuses of the vasculature promote specific features and functions in the niches, as reviewed by Hambardzumyan and Bergers. In addition to GSC maintenance, the niches could undergo dynamic alterations in a temporal and spatial manner and create a succession of tumor microenvironments to accommodate the aggressive growth of a tumor such as GBM into normal tissue, both during tumor progression and in response to therapeutic agents. In this context, some therapies could convert a tumor niche into another niche type instead of eliminating it, thereby losing their effectiveness. According to Hambardzumyan and Bergers, it is likely, for instance, that therapies such as radiation and cytotoxic chemotherapies, which create hypoxia and necrosis, may enhance hypoxic niches that will transition into perivascular tumor niches during tumor relapse. Therefore, the understanding of the crosstalk between GSCs and their niches, which supports GSC self-renewal, tumor invasion, and metastasis, as well as GSC escape from therapy, has become a promising target. In this sense, Mannino and Chalmers proposed that radioresistance is a result of interactions between these cells and microenvironmental factors, i.e., the “microenvironment - stem cell unit”. Brain hypoxia is known to be one of the most critical characteristics in the tumor microenvironment and is associated with the promotion of tumor progression and facilitation of angiogenesis, metabolism, and tumor radioresistance, in addition to triggering mechanisms such as hypoxia-inducible factor (HIF) signaling and epithelial-mesenchymal transition (EMT). HIF signaling was also reported to be pivotal in GSC regulation. Low oxygen levels were observed to prevent GSC differentiation, induce neurospheres, and maintain the potential of pluripotent embryonic and stemness markers. The link between hypoxic responses and GSCs was suggested by Li and coworkers, who found a differential response of GSCs to the HIF family of transcription factors, including promotion of their self-renewal. Likewise, a proof-of-concept study using HIF knockdown in GSCs resulted in reduced stemness in vitro and in vivo. It has also been described that hypoxia induced the expression of vascular endothelial growth factor (VEGF) in HIF1- and HIF2-dependent GSCs. A close relationship between CD133+ cells and vascular structures was also found in a study by Christensen and coworkers.

10Moreover, two independent groups showed that the CD133+ subpopulation is capable of de novo tumor vascularization through direct differentiation into endothelial cells, suggesting that a therapy targeting angiogenic factors would be required to inhibit GBM stem cells and tumor neovascularization. Finally, it has also been shown that GBM cells irradiated under orthotopic conditions have a higher capacity for DSB repair than GBM cells irradiated in vitro, which resulted in the induction of fewer γH2AX and 53BP1 foci in CD133+ cells than in CD133− cells. The authors also showed an increase in the percentage of CD133+ cells at 7 days after radiation, which persisted at the onset of neurologic symptoms, suggesting that CD133+ cells are relatively radioresistant under intracerebral growth conditions.

Role of autophagy in mediating radioresistance

11Autophagy is a conserved cellular process that is crucial for maintaining cellular homeostasis and survival and differentiation. Therefore, it is associated with a variety of pathologies. In contrast to apoptosis, autophagy is a double-edged sword that could be either protective or detrimental to cells, depending on the nature of the stimulus (nutrient and growth factor deprivation or an external insult like radiation) and the extent of autophagy induction. Recent studies suggest that autophagy has been recognized as frequently activated in cancer and mediates tumor cells’ response to anticancer therapy, especially radiotherapy, decreasing its efficacy by contributing to GSC maintenance and reducing ROS-associated DNA damage. Moreover, radiation preferentially activates autophagy in CD133+ cells and increases the levels of the autophagy-related proteins LC3, ATG5, and ATG12. The same was found in the radioresistant cell line, in which enhanced autophagic flux and silencing of the LC3A gene sensitized mouse xenografts to radiation. However, in a study examining the induction of autophagy by radiation and its role in the radioresistance of GSCs, the authors found that GSCs expressed lower levels of autophagy-related protein LC3 and radiation induced a low degree of autophagy in these cells. Moreover, a recent study showed that autophagy induction by the mammalian targets of rapamycin (mTOR) inhibitor rapamycin triggers GSC differentiation and enhances their radiosensitization in vitro and in vivo, with rapamycin thus becoming a promising tool for radiosensitization in glioma.

Role of repair mechanism mediating chemoresistance

12The resistance of GSCs to chemotherapeutic drugs has been well documented, yet the importance of DNA repair remains unclear. A recent study calls into question whether the differential and more efficient DNA repair system is specific to all CSCs, since the effects of TMZ require efficient DNA repair (mismatch repair system). Moreover, the extensive heterogeneity within GBM can complicate the role of the DNA repair system in GSCs. The DNA repair protein MGMT is the best-characterized repair protein and is a crucial modulator of TMZ chemoresistance in GBM. MGMT is expressed in GBM at various levels, and reports of its expression in the GSC compartments remain conflicting. Nevertheless, there is consensus that MGMT expression substantially increases the resistance of GSC. A recent report showed MGMT expression in half of the CD133+ cell lines tested, and the majority of these cell lines were resistant to TMZ. This result may suggest the presence of an alternative MGMT-independent mechanism of therapeutic resistance.

Role of multidrug mediating chemoresistance

13Another mechanism involved in chemoresistance is multidrug resistance. However, its role in GSCs remains an open question. Normal and cancer stem cells have higher expression levels of several ABC transporters, which confer them with efflux ability for the fluorescent dye Hoechst 33342 and helps GBMs with the efflux of antineoplastic drugs. In line with this, increased ABCG1 expression was reported in TMZ-induced cells (the side population cells in flow cytometry that present the GSC phenotype), and enhanced expression of multidrug resistance 1 (MDR1) was found in the chemoresistant phenotype of CD133+ GSCs compared to bulk CD133−. Although ABCB1 can be an independent predictor for TMZ responsiveness, there is conflicting data regarding TMZ transport by these proteins. Bleu and coworkers showed that TMZ is not a substrate for the ABCG1 transporter in murine glioma cells.

14On the other hand, ABCG2/BCRP and ABCB1/MDR1 overexpression in GSCs was correlated with higher resistance of GSCs to chemotherapeutic drugs. Accordingly, the use of an ABC transporter inhibitor, such as verapamil, can decrease temozolomide, doxorubicin, and mitoxantrone resistance in GSCs. Besides, melatonin (N-acetyl-5-methoxytryptamine) increased methylation levels of the ABC transporter ABCG2/BCRP promoter, promoting a synergistic toxic effect with TMZ on GSCs and A172 malignant glioma cells. Moreover, reversan, an inhibitor of the MRP1 protein, increased the sensitivity of primary and recurrent GBM cells to TMZ treatment; however, this effect has not yet been evaluated exclusively in GSCs.

Role of apoptosis and autophagy in mediating chemoresistance

15The mechanisms of action of TMZ, such as apoptosis, senescence, and autophagy, have also been described in GSCs. Prolonged treatment with TMZ can induce p53 and p21WAF1/Cip1 and cell cycle arrest (G2/M arrest), although genetic background dependence is observed in GBM cell lines. Continued treatment also promotes apoptosis, but senescence is the major process observed in glioma and melanoma tumors or cell lines. Concerning apoptosis, following TMZ exposure, higher expression levels of antiapoptotic genes were observed in GSCs than in differentiated cell lines, suggesting a possible link between GSC chemoresistance and antiapoptotic factors. It was also reported that drug resistance observed in GSCs might depend on abnormalities in the cell death pathway, such as the overexpression of antiapoptotic factors or silencing of key death effectors. The autophagy process or autophagic cell death induction can also be observed in response to TMZ and contributes to glioma chemoresistance and TMZ treatment failure.

16Moreover, in GSCs obtained from freshly resected GBM specimens, the expression of autophagy-related proteins (i.e., Beclin-1, ATG55, and LC3) was decreased in CD133+ cells compared with CD133− cells after TMZ exposure. The authors suggested that GSCs might not be susceptible to classical pathways of autophagy. On the other hand, rapamycin induces the differentiation of GSCs by activating autophagy. Increased rates and numbers of neurospheres in the rapamycin group compared with other groups were also reported. Additionally, stem/progenitor cell and differentiation markers were downregulated and upregulated in rapamycin-treated cells, respectively. These data suggest that apoptosis and autophagy might contribute to GSC chemoresistance.

Role of Notch and Sonic hedgehog pathways in mediating chemoresistance

17The increased expression of proteins of the Notch and Sonic hedgehog (SHH) pathways in CD133+ cells compared with GBM cells has already been described. The comparison between treated and non-treated CD133+ primary GBM cells showed upregulated expression of the NOTCH 1, NCOR2, HES1, HES5, and GLI1 genes after TMZ treatment, suggesting the increased activity of these pathways. Moreover, the use of Notch or SHH inhibitors with TMZ reversed the resistance to TMZ.

Epithelial-mesenchymal transition (EMT) mediates GBM chemoresistance

18The epithelial-mesenchymal transition process can also contribute to GBM chemoresistance. This was exploited through the gene ZEB1, an EMT regulator, and a known regulator of stemness and SOX2 in solid tissue cancers. In GBM, the overexpression of the ZEB1 gene induced the expression of MGMT, resulting in greater tumor chemoresistance and also induced the expression of SOX2 and OLIG2, resulting in greater stemness and higher capacity for tumor formation.

Other mechanisms mediating chemoresistance—extrinsic pathways

19Previous studies reported that TMZ might eliminate CSCs under in vitro conditions. However, patients treated with TMZ, present no stabilized disease or recurrence, leading to fatal relapses, suggesting that other mechanisms, such as residual CSC survival, may occur in vivo. Other extrinsic factors, such as the microenvironment, contribute to the chemoresistance of solid tumors. Hjelmeland and coworkers demonstrated that exposure to an acidic pH environment promoted malignancy in GBM through the induction of a GSC phenotype. Moreover, cell-cell interactions and IL-6 protein expression constitute indirect evidence suggesting that these mechanisms may be relevant for GSCs. Several reports suggest that tumor cell stemness could be induced by tumor microenvironments such as hypoxia and drugs such as TMZ. In line with this, tumor cells can acquire CSC properties. A recent report showed essential data concerning the origin, development, and maintenance of the GSC population after TMZ treatment. In this study, the authors achieve the conversion of non-GSCs to GSCs, both in vitro and in vivo, after long-term exposure to clinically relevant doses of TMZ. They showed that newly formed GSCs expressed molecular markers associated with parental GSCs, displayed a high rate of tumor engraftment and had a more invasive phenotype. These data suggest that the stemness of GSCs may be governed by cellular plasticity and that TMZ can stimulate the dedifferentiation of non-GSCs, explaining the high rates of tumor recurrence after conventional therapy.

Current strategies targeting cancer stem cells

20The discovery of pathways essential for modulating stemness properties has contributed to the identification of several molecules that could eliminate GSCs, including new antineoplastic agents from natural sources. A summary of current potential treatments is presented in Table 1 and Fig. 3.

21Given the requirement for hedgehog (Hh) signaling in GSCs, a recent study investigated cyclopamine (11-deoxojervine) (1) and guggulsterone (2). Cyclopamine can specifically inhibit the Hh pathway as well as the side and aldefluor-positive populations, resulting in cultures unable to form colonies in preclinical studies and GSCs sensitized to radiation. Another important protein able to target different pathways (Hedgehog, Notch, and β-catenin) is casein kinase 2 (CK2). In GBM, CK2 expression and activity lead to tumor suppressor inhibition and oncogene activation contributing to gliomagenesis. Moreover, CK2 inhibition promotes O6-methylguanine-DNA-methyltransferase downregulation and sensitizes glioma cells to TMZ. CX-4945 (3) is potent, selective, and highly bioavailable compared to other CK2 inhibitors. This novel molecule and its analogs target several GSC factors and markers and exhibit promising results in preclinical studies of several types of tumors, in vivo models and human clinical trials.

22Regarding the cell cycle and DNA damage repair, there are several CHK1 and CHK2 inhibitors; CHK1 inhibitors in clinical development include SCH 900776 (NCT00779584) (4) and SAR-020106 (5). AZD7762 (NCT00413686) (6) and debromohymenialdisine (DBH) (7) are novel potent checkpoint kinase inhibitors that inhibit both CHK1 and CHK2. AZD7762 was shown to potentiate chemotherapy response in several different settings and resulted in the abrogation of DNA damage-induced cell cycle arrest in vitro and in vivo in combination with DNA-damaging agents. The use of DBH and radiation treatment is synergistic: together they are able to abrogate the radioresistance of CD133+ cells, suggesting new options for combination radiotherapy.

23EGFR is a crucial receptor in the protocols described for growing GSCs, making clear that this pathway is necessary for GSC survival. Thus, it would be rational to use EGFR inhibitors to promote the inhibition of GSC proliferation and self-renewal and induce cell death. First-generation EGFR inhibitors such as erlotinib (8) and gefitinib (9) have been used in the clinical treatment of glioma patients, although less than 20% of patients presented a response to these treatments. However, EGFR inhibition has been observed to enhance the chemo- and radiosensitivity of human glioma CSCs. It is believed that the low response to these inhibitors is associated with loss of the tumor suppressor PTEN, which is usually deleted or mutated in gliomas and plays a critical role in maintaining neural precursor cells via activation of the mTOR pathway. Clinical results with rapamycin (10) have been described in patients with high-grade GBM and have demonstrated that treatment with rapamycin or combination with EGFR inhibitors may provide an alternative treatment for TMZ-resistant gliomas, regardless of EGFR status.

24Related to autophagy, the cell death and survival response can be influenced to favor cell death through several therapies that inhibit autophagy processes. Chloroquine (CQ) (11) is an applicable autophagy inhibitor known to trigger apoptosis in conventional autophagic tumor cells and to improve mid-term survival in glioma when administered in addition to conventional therapy. Regarding GSCs, triple combinations of γIR, low-dose CQ, and PI3K/Akt pathway inhibitors or high-dose CQ alone induced strong cytotoxic effects in radioresistant GSCs. Moreover, inhibitors such as bafilomycin A1 or beclin 1 and ATG5 shRNAs also sensitize GSCs to radiation and reduce their viability and capacity to form neurospheres. Likewise, radiation and the inhibition of αv integrin by cilengitide (12), which is currently in clinical evaluation, induce autophagy in GSCs, increasing cytotoxicity and reducing cell survival.

25In addition, the association of mTOR inhibitors and radiation led authors to evaluate the effects of AZD2014 (13), a competitive dual mTORC1/2 inhibitor, unlike rapamycin, an allosteric inhibitor, on the radiosensitivity of GSCs in in vitro and in vivo studies. Beyond these properties, AZD2014 also penetrates the blood-brain barrier and has been reported in a Phase I clinical trial as a single agent. The authors showed that AZD2014-mediated radiosensitization in GSCs promoted the inhibition of DSB repair as evaluated by a clonogenic assay according to γH2AX foci. Additionally, in GSC-initiated orthotopic xenografts, AZD2014, when combined with radiation, significantly prolonged mouse survival even when administered for only 3 days. These data indicate that AZD2014 may be a radiosensitizer applicable to GBM therapy.

26Moreover, other molecules can decrease the stemness properties of GSCs, including eckol (14), Nordy (15), resveratrol (16), STX-0119 (17), ER400583-00 (18), WP1193 (19), angiogenesis inhibitors, all-trans-retinoic acid (20), and Tanshinone IIA (21). Some of these molecules are linked to targets the microenvironment and thus indirectly modulate the stemness properties of cancer cells. However, these drugs cannot be used for a specific tumor type because the role of each niche in different tumor types and how they differ from one another is not yet known. This class includes molecules that primarily target angiogenesis and hypoxia.

27Eckol (14), a phlorotannin compound from Ecklonia species, has been shown to attenuate in vitro anchorage-independent growth on soft agar and reduce sphere formation and GSC markers. Moreover, the CD133+ subpopulation and self-renewal-related proteins were decreased in response. The authors suggested that eckol activity could target PI3K/Akt and MAPK signaling pathways. Importantly, eckol treatment also decreases the resistance of GSCs to IR and TMZ and tumor formation in xenograft mice.

28The synthetic dl-nordihydroguaiaretic acid compound Nordy (15) was also shown to inhibit self-renewal properties, induce GSC differentiation, and decrease the GSC pool in vitro and in vivo. Alox-5 is a Nordy target that promotes the invasion and proliferation inhibition of GSCs. Moreover, Nordy promotes GFAP upregulation, angiogenesis inhibition, and stemness marker downregulation.

29Regarding pluripotency, signal transducer and activator of transcription 3 (STAT3), which is associated with the cell cycle and survival, regulation, immune response, and differentiation, has been described as a critical initiator and regulator of tumorigenic transformation in GBM and implicated among GSC maintenance factors. STAT3 has been related to oncogenic or tumor-suppressive roles in GBM depending on the tumor genotype. These novel therapies may be the basis for the next generation of GBM treatment. STAT3 signaling includes small molecules such as oleanolic acid (22), STX-0119 (13), and WP1066 (23). Resveratrol (16) (RV), a polyphenol in grapes, is known to be a potential noncytotoxic tumor-preventive drug targeting STAT3 signaling. In glioma, RV can induce apoptosis, enhance radiosensitivity in the CD133+ cell population, and decrease tumorigenicity in xenotransplant experiments. Furthermore, RV was able to inhibit cell proliferation and decrease cell motility by modulating the Wnt signaling pathway and EMT activators.

30Another novel molecule recently investigated is WP1066 (23), an analog of the natural product caffeic acid benzyl ester and a potent STAT3 pathway inhibitor. In glioma, this potent small-molecule inhibitor showed promise as a therapeutic agent by targeting GSCs and will be investigated in a clinical trial for patients with recurrent malignant glioma and brain metastasis from melanoma (recruiting, ClinicalTrials.gov). In addition, WP1066 can cross the blood-brain barrier and is orally bioavailable.

31Antiangiogenic agents that disrupt GBM-initiating cell maintenance have been widely investigated, but so far, only modest results have been obtained. Moreover, some reports have indicated that glioma develops resistance to the employed antiangiogenic treatments. To date, in highly vascular tumors such as gliomas, angiogenesis inhibition has improved progression-free survival, although no cure has been achieved. Clinical trials using bevacizumab (BEV) (24) and cediranib (AZD2171) (25) (Phase I) alone or in combination have demonstrated efficacy in GBM patients. In in vivo experimental studies with mice, BEV treatment decreased GSCs and the growth rate of GBMs.

32Regarding clinical trials, BEV (24) has been combined with irinotecan (Phase II) and pazopanib, also an oral multitarget angiogenesis inhibitor (GW786034) (Phases I and II). A study also demonstrated that BEV or interferon-beta could enhance radiosensitivity in orthotopic GBM. However, recent studies suggest that inhibition of angiogenesis is even a driving force for tumor conversion to a higher malignancy state, inducing a phenotypic change from single-cell infiltration to migration of cell clusters along normal blood vessels, which is reflected in higher invasion, enhanced metastatic activity and dissemination.

33Moreover, antiangiogenic therapy changes tumor vasculature, leading to hypoxia. The hypoxia phenotype has been demonstrated as a marker of antiangiogenic therapy resistance by HIF-1α and stromal-cell derived factor-1α (SDF-1α) upregulation leading to the recruitment of various pro-angiogenic bone marrow-derived cells. For hypoxia modulation, compelling data demonstrate that the downregulation of HIF2-α can increase stem cell/pluripotency markers, neurosphere formation, and the VEGF pathway. Thus, several molecules that inhibit or indirectly modulate the expression of HIF-1 have been investigated, although they showed little efficacy either alone or in combination with standard antitumor agents. For instance, honokiol (26), manassantin (27) B from Saururus cernuus and Saururus chinensis, curcumin from Curcuma spp. (28), resveratrol (16), SU5416 (29), and ER400583-00 (18) are inhibitors that have been developed.

34Honokiol (26) is one of the biphenolic bioactive compounds isolated from Magnolia officinalis, possessing multifunctional activities in addition to crossing the blood-brain barrier. Honokiol specifically inhibits PI3K/mTOR signaling activation in gliomas, promotes the elimination of GSCs, and reverses TMZ resistance using GBM8401 SP cells, which appear to have higher expression of MGMT and to be more resistant to TMZ. This inhibition is accompanied by a greater induction of apoptosis and reduced expression levels of EGFR, CD133, and Nestin, suggesting that honokiol might have clinical benefits for GBM patients, mainly those who are refractory to TMZ treatment.

35Furthermore, several agents, such as cannabinoids (30), are known to exert antitumor action on GBM by apoptosis induction and tumor angiogenesis inhibition and have been recently evaluated in GSC differentiation control. The study provides further support for the hypothesis that cannabinoid changes reduce glioma initiation (neurosphere formation and cell proliferation) in vivo. These effects were greater in combination with TMZ and correlated with an increase in cell differentiation. Another strategy to reduce the tumorigenic potential of GSCs and promote differentiation is to induce bone morphogenic proteins (BMP) signaling. The potential of BMP induction of astrocyte differentiation from normal neural precursors has been reported in vitro and in vivo. Most importantly, BMP4 has been shown to trigger a significant decrease in GSCs. Even with BMP signaling, it was identified that BMP2 heightens sensitivity to TMZ in GSCs in which MGMT expression was described as directly downregulated by HIF-1α at the transcriptional level.

36The epigenetic modulation of histone acetylation by histone deacetylase (HDAC) activity has been associated with several cancer types. The HDAC inhibitor, vorinostat (suberoylanilide hydroxamic acid, SAHA) (31), and sahaquine (32) are currently in Phase I clinical trials in GBM. In vitro, SAHA has shown antiproliferative effects by blocking G1/S phase progression, increasing the levels of apoptosis-related genes and inducing the expression of cleaved PARP and p-γH2AX in GSCs. Sahaquine inhibits HDAC6, leading to a reduction in the viability and invasiveness of glioblastoma tumors and brain tumor stem cells. Most importantly, HDAC inhibitor treatment under culture proliferation conditions suggests the induction of differentiated cell states in adult mouse neural stem cells.

37In addition, all-trans-retinoic acid (ATRA) (20), a differentiating agent used in clinical practice, is a natural compound derivative of retinoic acid, also known as vitamin A. Some findings reported its capacity for differentiating stem cells as well as normal neural progenitor cells and downregulating the expression of the stem cell marker nestin. An additional study revealed that a combination of ATRA and paclitaxel was able to synergistically reduce GBM tumor growth in both in vivo and in vitro models. GSCs differentiated into glial and neuronal lineages even at low concentrations of ATRA. Moreover, ATRA decreased proliferation and self-renewal of neurospheres and promoted apoptosis at high concentrations, targeted ERK1/2 signaling, induced cell cycle arrest at the G1/G0 to S transition, decreased cyclin D1 expression, and increased p27 expression.

38Another agent with antiproliferative and prodifferentiation effects in GSCs is aurora-A kinase (AURK), a crucial serine-threonine kinase observed to be variably overexpressed in gliomas. AURK is also a vital kinase that governs self-renewal capacity in GBM tumorsphere cultures. These authors used a pan-AURK inhibitor, VX680 (33), followed by radiation, in cell culture and xenograft models, and demonstrated the induction of apoptosis and reduction of tumor growth. Hong and coworkers also demonstrated that MLN8237 (alisertib) (34), a highly selective AURK inhibitor, inhibits colony formation in GSCs and potentiates the effects of radiation and TMZ in glioblastoma monolayers and GSCs. Importantly, MLN8237 is relatively non-toxic to normal human astrocytes.

39Another emerging antiglioma drug is metformin (35), a drug used mainly for the therapy of type 2 diabetes and polycystic ovary syndrome. Metformin treatment in vitro was able to block cell cycle progression (G0/G1 phase), although cell death was not observed in GBMs. In a recent report, metformin selectively and remarkably affects GSC viability in vitro. The authors showed that AKT and the transcription factor forkhead box O3 (FOXO3) are involved in the molecular mechanism of metformin activity in GSCs. The effects of metformin were also validated in preclinical glioma orthotopic animal models, in which metformin administration resulted in a decrease of the self-renewing properties and tumor-initiating subpopulation. Clinical trials on the use of metformin alone and cancer treatment (including glioma) and prevention are ongoing.

40Maruccia and coworkers reviewed exciting results obtained with forty-nine different natural products, including flavonoids, alkaloids, polyketides, and acid derivatives. One terpene or terpenoid compound class that has been reported in GSCs is the retinoic acids (all-trans), which are potent differentiating agents. The retinoic acids induce the in vitro differentiation of GSCs and impair the secretion of angiogenic cytokines and GSC motility, promoting synergistic therapy. The antitumor mechanism is associated with the downregulation of Wnt/-catenin signaling. Well-characterized polyketides are telomestatin (36) and derivatives from Streptomyces anulatus, able to induce apoptosis and impair migration potential of GSCs in vitro and in vivo and to moderately change non-GSCs and normal neural precursors. Moreover, these macrocyclic compounds also promoted telomeric and nontelomeric DNA damage in GSCs. Two different alkaloids have been reported to be active against GSCs: cyclopamine (1) from Veratrum californicum and harmine (37) from Peganum harmala. It was demonstrated that harmine inhibits self-renewal and induces GSC differentiation. In particular, harmine inhibits neurosphere formation of human primary glioblastoma GSCs and AKT phosphorylation.

Conclusion

41The development of effective therapy for GBM remains a significant challenge in molecular oncology due to several questions mentioned above. Here, we have discussed several bioactive products that have been reported to modulate GSCs and shown to be essential for therapeutic applications. Although the detailed underlying mechanisms are unknown, bioactive products hold promise for the development of new drugs to treat glioma. Advances in understanding the pathomechanisms of glioma and the identification of GSC properties and therapeutic targets in the GSC subpopulation offer new directions for the development of novel therapies, either isolated or in combination, using personalized targeting for primary brain tumors, which is further emphasized in strategies for basic and translational research with natural compounds.

42Papers of special note have been highlighted as either of interest or of considerable interest to readers

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Not in our library10.1016/j.taap.2011.04.006
108.
Wang B, Yu SC, Jiang JY, et al. An inhibitor of arachidonate 5-lipoxygenase, Nordy, induces differentiation and inhibits self-renewal of glioma stem-like cells. Stem Cell Rev Rep. 2011;7(2):458-470.
Not in our library10.1007/s12015-010-9175-9
109.
Yang YP, Chang YL, Huang PI, et al. Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis. J Cell Physiol. 2012;227(3):976-993.
Not in our library10.1002/jcp.22806
110.
Okamoto K, Ito D, Miyazaki K, et al. Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor. Int J Mol Med. 2012;29(4):541-549.
Not in our library10.3892/ijmm.2011.875
111.
Sai K, Wang S, Balasubramaniyan V, et al. Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway. J Neuro-Oncol. 2012;107(3):487-501.
Not in our library10.1007/s11060-011-0786-z
112.
Torquato HF, Goettert MI, Justo GZ, et al. Anti-Cancer Phytometabolites targeting Cancer stem cells. Curr Genomics. 2017;18(2):156-174.
Not in our library10.2174/1389202917666160803162309
113.
Cho DY, Lin SZ, Yang WK, et al. Targeting cancer stem cells for treatment of glioblastoma multiforme. Cell Transplant. 2013;22(4):731-739.
Not in our library10.3727/096368912x655136
114.
Dixit D, Ghildiyal R, Anto NP, et al. Guggulsterone sensitizes glioblastoma cells to sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NFkappaB dependent manner. Cancer Lett. 2013;336(2):347-358.
Not in our library10.1016/j.canlet.2013.03.025
115.
Bates SE. Drugs that target the stemness pathways. Clin Cancer Res. 2010;16(12):3105.
Not in our library10.1158/1078-0432.ccr-10-1127
116.
Curran T. Reproducibility of academic preclinical translational research: lessons from the development of Hedgehog pathway inhibitors to treat cancer. Open Biol. 2018;8(8):180098.
Not in our library10.1098/rsob.180098
117.
Che J, Zhang FZ, Zhao CQ, et al. Cyclopamine is a novel hedgehog signaling inhibitor with significant anti-proliferative, anti-invasive and anti-estrogenic potency in human breast cancer cells. Oncol Lett. 2013;5(4):1417-1421.
Not in our library10.3892/ol.2013.1195
118.
Hedgehog Signaling in the Maintenance of Cancer Stem Cells · 2015
No notice
119.
Nitta RT, Gholamin S, Feroze AH, et al. Casein kinase 2alpha regulates glioblastoma brain tumor-initiating cell growth through the beta-catenin pathway. Oncogene. 2015;34(28):3688-3699.
Not in our library10.1038/onc.2014.299
120.
Liu X, Chen J, Li W, et al. Inhibition of casein kinase II by CX-4945, but not yes-associated protein (YAP) by verteporfin, enhances the antitumor efficacy of Temozolomide in Glioblastoma. Transl Oncol. 2020;13(1):70-78.
Not in our library10.1016/j.tranon.2019.09.006
121.
Pagano MA, Bain J, Kazimierczuk Z, et al. The selectivity of inhibitors of protein kinase CK2: an update. Biochem J. 2008;415(3):353-365.
Not in our library10.1042/bj20080309
122.
Sharma V, Hupp CD, Tepe JJ. Enhancement of chemotherapeutic efficacy by small molecule inhibition of NF-kappaB and checkpoint kinases. Curr Med Chem. 2007;14(10):1061-1074.
Not in our library10.2174/092986707780362844
123.
G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer · 2008
No notice
124.
Chumsri S, Shah P. Radiation resistance of cancer stem cells as an obstacle in cancer therapy. Mol Cell Pharmacol. 2013;5(1):39-49.
Not in our library
125.
Patties I, Kallendrusch S, Bohme L, et al. The Chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment. J Exp Clin Cancer Res. 2019;38(1):420.
Not in our library10.1186/s13046-019-1434-2
126.
Zabludoff SD, Deng C, Grondine MR, et al. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol Cancer Ther. 2008;7(9):2955-2966.
Not in our library10.1158/1535-7163.mct-08-0492
127.
Signore M, Pelacchi F, di Martino S, et al. Combined PDK1 and CHK1 inhibition is required to kill glioblastoma stem-like cells in vitro and in vivo. Cell Death Dis. 2014;5:e1223.
Not in our library10.1038/cddis.2014.188
128.
Facchino S, Abdouh M, Bernier G. Brain cancer stem cells: current status on glioblastoma multiforme. Cancers. 2011;3(2):1777-1797.
Not in our library10.3390/cancers3021777
129.
Soeda A, Inagaki A, Oka N, et al. Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells. J Biol Chem. 2008;283(16):10958-10966.
Not in our library10.1074/jbc.m704205200
130.
Liffers K, Lamszus K, Schulte A. EGFR amplification and glioblastoma stem-like cells. Stem Cells Int. 2015;2015:427518.
Not in our library10.1155/2015/427518
131.
Jun HJ, Bronson RT, Charest A. Inhibition of EGFR induces a c-MET-driven stem cell population in glioblastoma. Stem Cells. 2014;32(2):338-348.
Not in our library10.1002/stem.1554
132.
Lima FR, Kahn SA, Soletti RC, et al. Glioblastoma: therapeutic challenges, what lies ahead. Biochim Biophys Acta. 2012;1826(2):338–49.
Not in our library10.1016/j.bbcan.2012.05.004
133.
Fenton TR, Nathanson D, Ponte de Albuquerque C, et al. Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. Proc Natl Acad Sci U S A. 2012;109(35):14164-14169.
Not in our library10.1073/pnas.1211962109
134.
Kaza N, Kohli L, Roth KA. Autophagy in brain tumors: a new target for therapeutic intervention. Brain Pathol. 2012;22(1):89-98.
Not in our library10.1111/j.1750-3639.2011.00544.x
135.
Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol. 2008;26(18):3015–24.
Not in our library10.1200/jco.2007.15.7164
136.
Prados MD, Chang SM, Butowski N, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27(4):579-584.
Not in our library10.1200/jco.2008.18.9639
137.
Pang LY, Saunders L, Argyle DJ. Epidermal growth factor receptor activity is elevated in glioma cancer stem cells and is required to maintain chemotherapy and radiation resistance. Oncotarget. 2017;8(42):72494-72512.
Not in our library10.18632/oncotarget.19868
138.
Zhang I, Beus M, Stochaj U, et al. Inhibition of glioblastoma cell proliferation, invasion, and mechanism of action of a novel hydroxamic acid hybrid molecule. Cell Death Discov. 2018;4:41.
Not in our library10.1038/s41420-018-0103-0
139.
PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma · 2016
No notice
140.
Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma · 2008
No notice
141.
Reardon DA, Desjardins A, Vredenburgh JJ, et al. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. J Neuro-Oncol. 2010;96(2):219-230.
Not in our library10.1007/s11060-009-9950-0
142.
Chong DQ, Toh XY, Ho IA, et al. Combined treatment of Nimotuzumab and rapamycin is effective against temozolomide-resistant human gliomas regardless of the EGFR mutation status. BMC Cancer. 2015;15:255.
Not in our library10.1186/s12885-015-1191-3
143.
Folkins C, Man S, Xu P, et al. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 2007;67(8):3560-3564.
Not in our library10.1158/0008-5472.can-06-4238
144.
Campos B, Wan F, Farhadi M, et al. Differentiation therapy exerts antitumor effects on stem-like glioma cells. Clin Cancer Res. 2010;16(10):2715-2728.
Not in our library10.1158/1078-0432.ccr-09-1800
145.
Yang L, Guo H, Dong L, et al. Tanshinone IIA inhibits the growth, attenuates the stemness and induces the apoptosis of human glioma stem cells. Oncol Rep. 2014;32(3):1303-1311.
Not in our library10.3892/or.2014.3293
146.
Manandhar B, Paudel P, Seong SH, et al. Characterizing Eckol as a therapeutic aid: a systematic review. Mar Drugs. 2019;17(6):1–31.
Not in our library10.3390/md17060361
147.
Yang X, Cui W, Yu S, et al. A synthetic dl-nordihydroguaiaretic acid (Nordy), inhibits angiogenesis, invasion and proliferation of glioma stem cells within a zebrafish xenotransplantation model. PLoS One. 2014;9(1):e85759.
Not in our library10.1371/journal.pone.0085759
148.
de la Iglesia N, Puram SV, Bonni A. STAT3 regulation of glioblastoma pathogenesis. Curr Mol Med. 2009;9(5):580–90.
Not in our library10.2174/156652409788488739
149.
Brastianos PK, Batchelor TT. Vascular endothelial growth factor inhibitors in malignant gliomas. Target Oncol. 2010;5(3):167-174.
Not in our library10.1007/s11523-010-0158-1
150.
Javan MR, Khosrojerdi A, Moazzeni SM. New insights into implementation of mesenchymal stem cells in cancer therapy: prospects for anti-angiogenesis treatment. Front Oncol. 2019;9:840.
Not in our library10.3389/fonc.2019.00840
151.
Binello E, Germano IM. Targeting glioma stem cells: a novel framework for brain tumors. Cancer Sci. 2011;102(11):1958-1966.
Not in our library10.1111/j.1349-7006.2011.02064.x
152.
Wenger JB, Santos N, Liu Y, et al. Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma? Oncol Rev. 2011;5(3):177-184.
Not in our library10.4081/oncol.2011.177
153.
Cao Z, Fang J, Xia C, et al. Trans-3,4,5′-Trihydroxystibene inhibits hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in human ovarian cancer cells. Clin Cancer Res. 2004;10(15):5253-5263.
Not in our library10.1158/1078-0432.ccr-03-0588
154.
Choi H, Chun YS, Kim SW, et al. Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Mol Pharmacol. 2006;70(5):1664–71.
Not in our library10.1124/mol.106.025817
155.
Wojton J, Elder J, Kaur B. How efficient are autophagy inhibitors as treatment for glioblastoma? CNS Oncol. 2014;3(1):5-7.
Not in our library10.2217/cns.13.52
156.
Chresta CM, Davies BR, Hickson I, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70(1):288-298.
Not in our library10.1158/0008-5472.can-09-1751
157.
Masliantsev K, Pinel B, Balbous A, et al. Impact of STAT3 phosphorylation in glioblastoma stem cells radiosensitization and patient outcome. Oncotarget. 2018;9(3):3968-3979.
Not in our library10.18632/oncotarget.23374
158.
Hussain SF, Kong LY, Jordan J, et al. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 2007;67(20):9630–6.
Not in our library10.1158/0008-5472.can-07-1243
159.
Martinez-Garcia M, Banerji U, Albanell J, et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012;18(17):4806-4819.
Not in our library10.1158/1078-0432.ccr-12-0742
160.
Flannery PC, DeSisto JA, Amani V, et al. Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma. Oncol Rep. 2018;39(2):455-464.
Not in our library10.3892/or.2017.6122
161.
Ashizawa T, Miyata H, Iizuka A, et al. Effect of the STAT3 inhibitor STX-0119 on the proliferation of cancer stem-like cells derived from recurrent glioblastoma. Int J Oncol. 2013;43(1):219-227.
Not in our library10.3892/ijo.2013.1916
162.
Mazurek M, Litak J, Kamieniak P, et al. Metformin as potential therapy for high-grade glioma. Cancers. 2020;12(1):1–29.
Not in our library10.3390/cancers12010210
163.
Nanegrungsunk D, Onchan W, Chattipakorn N, et al. Current evidence of temozolomide and bevacizumab in treatment of gliomas. Neurol Res. 2015;37(2):167–83.
Not in our library10.1179/1743132814y.0000000423
164.
Vredenburgh JJ, Desjardins A, Herndon JE, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253-1259.
Not in our library10.1158/1078-0432.ccr-06-2309
165.
Hadjipanayis CG, Van Meir EG. Tumor initiating cells in malignant gliomas: biology and implications for therapy. J Mol Med. 2009;87(4):363-374.
Not in our library10.1007/s00109-009-0440-9
166.
Lim YC, Kang HJ, Kim YS, et al. All-trans-retinoic acid inhibits growth of head and neck cancer stem cells by suppression of Wnt/beta-catenin pathway. Eur J Cancer. 2012;48(17):3310-3318.
Not in our library10.1016/j.ejca.2012.04.013
167.
Kim JE, Patel M, Ruzevick J, et al. STAT3 activation in glioblastoma: biochemical and therapeutic implications. Cancers. 2014;6(1):376-395.
Not in our library10.3390/cancers6010376
168.
Fujiwara Y, Komohara Y, Kudo R, et al. Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3. Oncol Rep. 2011;26(6):1533-1537.
Not in our library10.3892/or.2011.1454
169.
Ball S, Li C, Li PK, et al. The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells. PloS one. 2011;6(4):e18820.
Not in our library10.1371/journal.pone.0018820
170.
Chen JK, Taipale J, Cooper MK, et al. Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev. 2002;16(21):2743-2748.
Not in our library10.1101/gad.1025302
171.
McGee MC, Hamner JB, Williams RF, et al. Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation. Int J Radiat Oncol Biol Phys. 2010;76(5):1537-1545.
Not in our library10.1016/j.ijrobp.2009.12.010
172.
Li N, Maly DJ, Chanthery YH, et al. Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma. Mol Cancer Ther. 2015;14(2):419-428.
Not in our library10.1158/1535-7163.mct-14-0526
173.
Fan Y, Xue W, Schachner M, et al. Honokiol eliminates glioma/glioblastoma stem cell-like cells via JAK-STAT3 signaling and inhibits tumor progression by targeting epidermal growth factor receptor. Cancers. 2018;11(1):1–21.
Not in our library10.3390/cancers11010022
174.
Lin JW, Chen JT, Hong CY, et al. Honokiol traverses the blood-brain barrier and induces apoptosis of neuroblastoma cells via an intrinsic bax-mitochondrion-cytochrome c-caspase protease pathway. Neuro Oncol. 2012;14(3):302-314.
Not in our library10.1093/neuonc/nor217
175.
Crane C, Panner A, Pieper RO, et al. Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. J Immunother. 2009;32(6):585-592.
Not in our library10.1097/cji.0b013e3181a8efe6
176.
Lai IC, Shih PH, Yao CJ, et al. Elimination of cancer stem-like cells and potentiation of temozolomide sensitivity by Honokiol in glioblastoma multiforme cells. PLoS One. 2015;10(3):e0114830.
Not in our library10.1371/journal.pone.0114830
177.
Aguado T, Carracedo A, Julien B, et al. Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis. J Biol Chem. 2007;282(9):6854-6862.
Not in our library10.1074/jbc.m608900200
178.
Lee J, Son MJ, Woolard K, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13(1):69-80.
Not in our library10.1016/j.ccr.2007.12.005
179.
Xi G, Best B, Mania-Farnell B, et al. Therapeutic potential for bone morphogenetic protein 4 in human malignant glioma. Neoplasia. 2017;19(4):261-270.
Not in our library10.1016/j.neo.2017.01.006
180.
Piccirillo SG, Reynolds BA, Zanetti N, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444(7120):761-765.
Not in our library10.1038/nature05349
181.
Lopez-Valero I, Saiz-Ladera C, Torres S, et al. Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide. Biochem Pharmacol. 2018;157:266–74.
Not in our library10.1016/j.bcp.2018.09.007
182.
Taddei A, Roche D, Bickmore WA, et al. The effects of histone deacetylase inhibitors on heterochromatin: implications for anticancer therapy? EMBO Rep. 2005;6(6):520-524.
Not in our library10.1038/sj.embor.7400441
183.
Soliman ML, Smith MD, Houdek HM, et al. Acetate supplementation modulates brain histone acetylation and decreases interleukin-1beta expression in a rat model of neuroinflammation. J Neuroinflammation. 2012;9:51.
Not in our library10.1186/1742-2094-9-51
184.
Kim S, Chen J, Cheng T, et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2019;47(D1):D1102–9.
Not in our library10.1093/nar/gky1033
185.
Bar EE, Chaudhry A, Lin A, et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells. 2007;25(10):2524-2533.
Not in our library10.1634/stemcells.2007-0166
186.
Son YH, Song JS, Kim SH, et al. Pharmacokinetic characterization of CK2 inhibitor CX-4945. Arch Pharm Res. 2013;36(7):840-845.
Not in our library10.1007/s12272-013-0103-9
187.
Firat E, Weyerbrock A, Gaedicke S, et al. Chloroquine or chloroquine-PI3K/Akt pathway inhibitor combinations strongly promote gamma-irradiation-induced cell death in primary stem-like glioma cells. PLoS One. 2012;7(10):e47357.
Not in our library10.1371/journal.pone.0047357
188.
Weyerhauser P, Kantelhardt SR, Kim EL. Re-purposing chloroquine for glioblastoma: potential merits and confounding variables. Front Oncol. 2018;8:335.
Not in our library10.3389/fonc.2018.00335
189.
Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis · 2018
No notice
190.
Lomonaco SL, Finniss S, Xiang C, et al. Cilengitide induces autophagy-mediated cell death in glioma cells. Neuro-oncology. 2011;13(8):857-865.
Not in our library10.1093/neuonc/nor073
191.
Kahn J, Hayman TJ, Jamal M, et al. The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neuro Oncol. 2014;16(1):29-37.
Not in our library10.1093/neuonc/not139
192.
Akhavan D, Cloughesy TF, Mischel PS. mTOR signaling in glioblastoma: lessons learned from bench to bedside. Neuro-oncology. 2010;12(8):882-889.
Not in our library10.1093/neuonc/noq052
193.
Cilibrasi C, Riva G, Romano G, et al. Resveratrol impairs glioma stem cells proliferation and motility by modulating the Wnt signaling pathway. PLoS One. 2017;12(1):e0169854.
Not in our library10.1371/journal.pone.0169854
194.
Hussain AI, Anwar F, Rasheed S, et al. Composition, antioxidant and chemotherapeutic properties of the essential oils from two Origanum species growing in Pakistan. Rev Bras. 2011;21(6):943-952.
Not in our library
195.
Roodink I, Leenders WP. Targeted therapies of cancer: angiogenesis inhibition seems not enough. Cancer Lett. 2010;299(1):1-10.
Not in our library10.1016/j.canlet.2010.09.004
196.
Arbab AS. Activation of alternative pathways of angiogenesis and involvement of stem cells following anti-angiogenesis treatment in glioma. Histol Histopathol. 2012;27(5):549-557.
Not in our library10.14670/hh-27.549
197.
Morris PG. Bevacizumab is an active agent for recurrent high-grade glioma, but do we need randomized controlled trials? Anti-Cancer Drugs. 2012;23(6):579-583.
Not in our library10.1097/cad.0b013e3283528847
198.
Zhong XS, Zheng JZ, Reed E, et al. SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochem Biophys Res Commun. 2004;324(2):471-480.
Not in our library10.1016/j.bbrc.2004.09.082
199.
Hossain M, Banik NL, Ray SK. Synergistic anti-cancer mechanisms of curcumin and paclitaxel for growth inhibition of human brain tumor stem cells and LN18 and U138MG cells. Neurochem Int. 2012;61(7):1102-1113.
Not in our library10.1016/j.neuint.2012.08.002
200.
Ivanov VN, Wu J, Wang TJC, et al. Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and gamma-irradiation in human glioblastoma cells. Oncotarget. 2019;10(8):825-846.
Not in our library10.18632/oncotarget.26582
201.
Persano L, Pistollato F, Rampazzo E, et al. BMP2 sensitizes glioblastoma stem-like cells to temozolomide by affecting HIF-1alpha stability and MGMT expression. Cell Death Dis. 2012;3:e412.
Not in our library10.1038/cddis.2012.153
202.
Massard C, Deutsch E, Soria JC. Tumour stem cell-targeted treatment: elimination or differentiation. Ann Oncol. 2006;17(11):1620-1624.
Not in our library10.1093/annonc/mdl074
203.
Galanis E, Jaeckle KA, Maurer MJ, et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol. 2009;27(12):2052-2058.
Not in our library10.1200/jco.2008.19.0694
204.
Sung GJ, Kim SH, Kwak S, et al. Inhibition of TFEB oligomerization by co-treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells. J Pineal Res. 2019;66(3):e12556.
Not in our library10.1111/jpi.12556
205.
Zhou Q, Dalgard CL, Wynder C, et al. Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells. BMC Neurosci. 2011;12:50.
Not in our library10.1186/1471-2202-12-50
206.
Ying M, Wang S, Sang Y, et al. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene. 2011;30(31):3454-3467.
Not in our library10.1038/onc.2011.58
207.
Das A, Banik NL, Ray SK. Molecular mechanisms of the combination of retinoid and interferon-gamma for inducing differentiation and increasing apoptosis in human glioblastoma T98G and U87MG cells. Neurochem Res. 2009;34(1):87-101.
Not in our library10.1007/s11064-008-9669-x
208.
Guan K, Chang H, Rolletschek A, et al. Embryonic stem cell-derived neurogenesis. Retinoic acid induction and lineage selection of neuronal cells. Cell Tissue Res. 2001;305(2):171-176.
Not in our library10.1007/s004410100416
209.
Karmakar S, Choudhury SR, Banik NL, et al. Combination of N-(4-hydroxyphenyl) retinamide and genistein increased apoptosis in neuroblastoma SK-N-BE2 and SH-SY5Y xenografts. Neuroscience. 2009;163(1):286-295.
Not in our library10.1016/j.neuroscience.2009.06.037
210.
Karsy M, Albert L, Tobias ME, et al. All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. Anticancer Res. 2010;30(12):4915-4920.
Not in our library
211.
Carol H, Boehm I, Reynolds CP, et al. Efficacy and pharmacokinetic/pharmacodynamic evaluation of the aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer. Cancer Chemother Pharmacol. 2011;68(5):1291-1304.
Not in our library10.1007/s00280-011-1618-8
212.
Lehman NL, O'Donnell JP, Whiteley LJ, et al. Aurora a is differentially expressed in gliomas, is associated with patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas. Cell Cycle. 2012;11(3):489-502.
Not in our library10.4161/cc.11.3.18996
213.
Mannino M, Gomez-Roman N, Hochegger H, et al. Differential sensitivity of glioma stem cells to aurora kinase A inhibitors: implications for stem cell mitosis and centrosome dynamics. Stem Cell Res. 2014;13(1):135-143.
Not in our library10.1016/j.scr.2014.05.001
214.
Ansari MF, Hayat F, Inam A, et al. New antiprotozoal agents: synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl) methanone derivatives. Bioorg Med Chem Lett. 2017;27(3):460–465.
Not in our library10.1016/j.bmcl.2016.12.043
215.
Hong X, O'Donnell JP, Salazar CR, et al. The selective aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation. Cancer Chemother Pharmacol. 2014;73(5):983-990.
Not in our library10.1007/s00280-014-2430-z
216.
Zumbar CT, Usubalieva A, King PD, et al. The CNS penetrating taxane TPI 287 and the AURKA inhibitor alisertib induce synergistic apoptosis in glioblastoma cells. J Neuro-Oncol. 2018;137(3):481-492.
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228.
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Not in our library10.1007/s11060-012-1034-x

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