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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 4  |  Page : 159-164

Repurposing drugs for the treatment of glioma

Department of Neurosurgery, Shanghai General Hospital of Nanjing Medical University, Shanghai, China

Date of Submission12-Dec-2019
Date of Acceptance31-Dec-2019
Date of Web Publication23-Jan-2020

Correspondence Address:
Dr. Yaodong Zhao
100 Haining Road, Hongkou District, Shanghai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_26_19

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Glioma is the most common primary tumor of the central nervous system. In addition to traditional anticancer drugs, some common nonchemotherapeutic drugs have been considered by some scholars, such as nonsteroidal anti-inflammatory drugs, metformin, and statins. These drugs are often used for the treatment of noncancerous diseases. However, it was found that those drugs could be considered for the clinical treatment of glioma, especially in combination with chemotherapy drugs, which may improve the treatment effect. This process is called “repurposing.” Here, we aim to review these drugs and the literature. These “old drugs” have been used clinically for many years, and their safety and feasibility are high. Such combinations are expected to become a new strategy in chemotherapy for glioma in the clinic.

Keywords: Aldehyde dehydrogenase inhibitors, cyclooxygenase-2, deacetylase inhibitors, glioma, ion channels, metformin, repurposing drugs, statins

How to cite this article:
Xu C, Zhao Y, Wu C, Li L. Repurposing drugs for the treatment of glioma. Glioma 2019;2:159-64

How to cite this URL:
Xu C, Zhao Y, Wu C, Li L. Repurposing drugs for the treatment of glioma. Glioma [serial online] 2019 [cited 2023 Feb 3];2:159-64. Available from: http://www.jglioma.com/text.asp?2019/2/4/159/276699

  Introduction Top

Glioma is the most common primary tumor of the central nervous system. Although treatment for glioma has improved in recent years, survival has not improved. In addition to traditional anticancer drugs, some common nonchemotherapeutic drugs have been considered by some scholars, such as metformin and statins.[1],[2] These nonchemotherapeutic drugs are often used for the treatment of noncancerous diseases, and they have been used safely in the clinic for many years.[3],[4] Their toxicology and pharmacokinetics are relatively well known. This process is called “repurposing.” It was found that some of the drugs could be considered for the clinical treatment of glioma, especially in combination with chemotherapy drugs, which may improve the treatment effect.[1] Here, we aim to review relevant literature, find out these drugs, and identify their mechanisms of action, which might be helpful to researchers and clinicians to explore the combination strategy for glioma.

  Database Search Strategy Top

The articles on drugs in this review were retrieved by relevant keywords. English language, Chinese language, and full-text articles published in and before 2019 were included in this review. We searched databases such as PubMed to identify relevant publications. The literature search strategy was conducted as follows: six keywords: (1) Cyclooxygenase-2, (2) Drugs targeting ion channels, (3) Aldehyde dehydrogenase inhibitors, (4) Adenosine monophosphate-activated protein kinase pathway activators, (5) Deacetylase inhibitors, and (6) Statins were combined with glioma. Six queries were obtained. We screened the reference list of the included studies to identify other potentially useful studies. First, the titles and abstracts and then the full texts for keywords to find those that were potentially suitable were screened. The data extraction process focused on the information about the effects of each drug on tumors and gliomas. According to the important information provided in the literature, the literature search can be conducted again to obtain additional information.

  Cyclooxygenase-2 Top

Nonsteroidal anti-inflammatory drugs are used to treat acute and chronic pain by inhibiting the action of cyclooxygenase (COX).[5] Celecoxib, aspirin, and other nonsteroidal anti-inflammatory drugs are common and are used often in rheumatoid arthritis, osteoarthritis, and other diseases. Such drugs mainly relieve pain and inflammation through the COX-2/prostaglandin E2 (PGE2) pathway.[6] Interestingly, this pathway can also be targeted as an antitumor strategy.[7] The high expression of COX-2 in glioma is closely related to its proliferation, apoptosis, angiogenesis, metastasis, and immunodeficiency. PGE2 is the main metabolite of COX-2.[7]

Tumor immune escape is a major factor in the development of glioma.[8] When there are few tumor cells, it is not easy to illicit an immune response; however, when an immune response begins to develop, immune-suppressive factors are secreted into the microenvironment of glioma.[8] Factors such as PGE2, transforming growth factor-β, and interleukin-10 may suppress the immune response, leading to tumor cell immune escape.[9] COX-2 can inhibit the activity of macrophages, natural killer cells, and T cells and inhibit the production of cytokines such as interferon-y and interleukin-10 through its catalytic product, PGE2, which can increase the level of intracellular cyclic adenosine monophosphate.[10] Interleukin-10 can reduce the surface molecule expression of dendritic cells and inhibit the differentiation, maturation, and antigen-presenting abilities of dendritic cells such that they cannot activate T cells to recognize and kill tumor cells, which leads to tumor immune escape.[11]

In mouse glioma models, it was found that the tumor volume of the celecoxib treatment group was significantly smaller than that of the control group, and the expression of COX-2, vascular endothelial growth factor, and transforming growth factor-β protein in the tissue was decreased.[12] It has been experimentally confirmed that celecoxib treatment increases the sensitivity of malignant tumors to radiotherapy and chemotherapy, but the combination has not been translated into the clinic, and research is still in its infancy.[13]

  Drugs Targeting Ion Channels (Potassium Channels and Calcium Channels) Top

In clinical treatment, potassium channel blockers such as amiodarone and sotalol are often used to treat arrhythmias. They block voltage-sensitive potassium channels, reduce potassium ion flux, and prolong the action potential duration and refractory period.[14],[15] Calcium channel-targeting drugs, such as verapamil, inhibit extracellular calcium influx, lead to decreased myocardial contractility, reduce heart rate, relax vasculature, reduce blood pressure, etc., for the treatment of angina and arrhythmia.[16]

In the process of glioma development, potassium channels and calcium channels play different roles. They can participate in the proliferation, differentiation, migration, and apoptosis of tumor cells through different pathways.[17] They are also involved in the tumor cell cycle. Potassium channels act in the mitotic cycle of cells, mainly in the following aspects: mitosis increases the expression and activity of potassium channels; potassium channel activators stimulate cell mitosis; and blockers inhibit cell mitosis.[18] Similarly, the progression of the tumor cycle often depends on the intracellular basal concentration of Ca2+.[18] Ru et al.[19] analyzed calcium influx by voltage-gated potassium channels and found that it regulates the proliferation of U87 cells.

In order for metabolic activities of tumor cells to be carried out efficiently, they independently regulate the intracellular pH to form a weakly alkaline cytoplasmic environment, which is achieved by channels for molecules such as potassium ions.[20] Therefore, inhibition of ion channel activity can lower pH, increase endonuclease activity, cause DNA fragmentation between nucleosomes, limit the activation of proto-oncogenes, and enhance the susceptibility of tumor cells to various physical and chemical factors and chemotherapy drugs, thus increasing apoptosis.[20]

During the migration phase, glioma cells need to change their size and shape to effectively pass through the extracellular space, which is helpful for invading the barriers of normal cells.[21] When potassium ions flow out of the cell, the cell volume becomes smaller and cells migrate easily.[22] Glioma cells have an energy-dependent membrane protein, P-170, which is a calcium channel.[23] When a common chemotherapeutic drug enters the extracellular fluid and passively enters the tumor cell, depending on the concentration gradient, it will be pumped out by the P-170 protein, leading to a significant decrease in the effect of chemotherapy and drug resistance.[23] Nicardipine is a calcium ion antagonist that can be combined with P-170 to reduce drug efflux, increase intracellular drug concentration, and enhance drug effects.[24]

Common potassium channel drugs include sulfonylureas, such as glibenclamide,[25] and antiarrhythmic drugs such as amiodarone;[26] calcium channel drugs include dihydropyridines such as nicardipine and phenylalkylamines such as verapamil.[27] These drugs have been shown to be effective in regulating ion channels and can play a role in certain antitumor processes.[25],[26],[27] Moreover, nicardipine, when used in combination with chemotherapeutic drugs, can inhibit the high expression of adenosine triphosphate-binding cassette G2, which is one mechanism by which tumors become resistant to chemotherapy.[28] It was shown that treating a mouse glioma model with carmustine and verapamil led to tumor sizes that were significantly smaller than those seen with carmustine treatment alone.[29] Lou and Zhao[30] found that nimustine combined with nicardipine was effective in the treatment of advanced glioma.

  Aldehyde Dehydrogenase Inhibitors Top

Aldehyde dehydrogenase (ALDH) is mainly involved in the oxidative metabolism of aldehydes in cells.[31] Disulfiram is an ALDH1 inhibitor.[32] ALDH catalyzes the transformation of intracellular 9-cis-retinene into an important signaling molecule in the cell, retinoic acid. Retinoic acid can regulate a variety of biological processes in cells, including tumor cell proliferation, differentiation, and apoptosis and cell cycle arrest.[33] Moreover, ALDH is also involved in the epithelial–mesenchymal transition process of tumor cells.[34] Through this process, tumor cells can escape the lysis of T-cells, and this escape is closely related to the spread, recurrence, and progression of malignant tumors.[34]

In glioma stem cells, ALDH can promote the transformation of tumor stem cells from a neuronal pretype to an interstitial type, which significantly increases the malignant degree of the glioma.[35] ALDH can also increase the chemoresistance of cancer stem cells. After the chemotherapeutic drug enters the cell, its aldehyde group can be oxidized to the corresponding carboxylic acid, and the corresponding toxic substance is converted into a nontoxic form.[36] It can be seen that cancer stem cells with more ALDH are often more tolerant to chemotherapy than cells with less ALDH.[37] Therefore, the use of antitumor drugs after treatment with ALDH inhibitors can achieve superior results. These findings show that the application of ALDH inhibitors is important for combating tumors and delaying recurrence. Adam et al.[38] found that the colony-forming ability of ALDH1A1-positive glioma cells was significantly stronger than that of ALDH1A1-negative cells; in addition, the expression of ALDH1A1 is closely related to the Ki67 proliferation index, and the prognosis of patients with high expression is often poor. Lun et al.[39] found that disulfiram can be used to inhibit doxorubicin being pumped out of cells, leading to an increased concentration of doxorubicin in tumor cells and effectively enhancing the anticancer effect of doxorubicin. Rae et al.[40] studied malignant glioma cells and found that disulfiram could enhance the growth inhibition of tumor cells by radiation.

  Adenosine Monophosphate-Activated Protein Kinase Pathway Activators Top

A large number of clinical studies have found that the commonly used drug metformin can reduce the incidence of tumors in diabetic patients,[41],[42] and some studies have suggested that metformin has a small inhibitory effect on the growth of a variety of malignant diseases, such as glioma, breast cancer, and gastric cancer.[43],[44],[45] Metformin can induce apoptosis in gliomas by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway.[46]

AMPK is a protein kinase in cells, which is a receptor related to cellular energy.[47] When AMPK is activated, it may inhibit the growth of tumor cells through two pathways, namely decreasing intracellular cyclin D1 via the p53/p21 pathway and blocking the cell cycle in the G1 phase.[48] Mammalian target of rapamycin is one of the target proteins of AMPK, and activated AMPK can inhibit the activity of the target protein to promote apoptosis. When mammalian target of rapamycin activity is weakened, the downstream target molecules ribosomal protein S6 kinase and eukaryotic promoter 4E binding protein are dephosphorylated to reduce intracellular protein synthesis and cell growth.[49],[50]

Studies have shown that metformin can reverse the increase in Akt activity caused by temozolomide and that metformin can inhibit the mammalian target of rapamycin and its downstream signaling pathway, which is the main mechanism by which temozolomide and metformin synergistically clear germline stem cells.[51],[52],[53] Experimental studies suggest that the combination of temozolomide and metformin has a higher inhibition rate in treating glioma and more synergistic effects on glioma stem cells than monotherapy.[51],[54] Maraka's team[1] found that metformin is feasible and safe to use in combination with temozolomide for the treatment of glioblastoma by studying its use as an antiglioma agent.

  Deacetylase Inhibitors Top

In recent years, it has been found that sodium valproate can bind to the catalytic center of deacetylases and inhibit deacetylase and cellular kinase activity, thereby affecting histone acetylation, transcription, and DNA methylation to regulate gene transcription.[55] The mitogen- AMPK signaling pathway ultimately inhibits glioma angiogenesis and induces the differentiation and apoptosis of different tumor cells.[56] Some studies have shown that sodium valproate (deacetylase inhibitor) can decrease the viability of glioma stem cells, reduce the formation of glioma stem cells, and lead to the apoptosis of glioma stem cells.[57],[58]

At the same time, deacetylase inhibitors can also exert antitumor effects via multiple pathways, such as decreased invasiveness and migration of glioma cells and increased apoptosis of glioma cells, by inhibiting signal transduction and phosphorylation of activators.[57] Deacetylase inhibitors can also inhibit the activity of nuclear transcription factor-κB and induce the apoptosis of U266 cells by inhibiting the phosphorylation of the inhibitor of nuclear transcription factor-κB.[59] Studies have shown that high expression of cyclin D1 in glioma cells can lead to uncontrolled cell proliferation, and cyclin D1 can also bind to histone deacetylase to promote its own transcription.[60],[61],[62] After treatment with deacetylase inhibitors, the expression of cyclin D1 protein in glioma stem cells decreased, and the cell cycle was blocked in the G1 phase. The possible causes include the downregulation of the expression of cyclin D1 resulting in glioma stem cells being unable to enter S phase and the decrease in cyclin D1 gene expression induced via the inhibition of cyclin D1 and histone deacetylase binding.[62]

Deacetylase inhibitors, such as sodium valproate, are commonly used in the prevention and treatment of epilepsy.[63] However, they can stop the cell cycle, promote cell differentiation, induce apoptosis, and inhibit tumor cell migration and angiogenesis of tumor tissue, making deacetylase inhibitors possible candidates for antitumor adjuvant therapy.[56] After treatment of glioma stem cells with different concentrations of sodium valproate, the colony formation rate of glioma stem cells decreased significantly with increasing concentration, and the inhibitory effect was concentration dependent.[64] Sodium valproate can be used alone or in combination with the traditional chemotherapy drug temozolomide to treat gliomas with extremely high malignancy.[65] It has been reported that valproate–temozolomide synergistically inhibits the proliferation and migration of temozolomide-sensitive glioma cell lines (T98 and U138) and induces apoptosis and autophagy.[66] Combination therapy can reduce the growth of tumors in glioma transplant models.[66] In addition, Phase II clinical trials have shown that combination treatments with valproate, radiotherapy, and temozolomide when compared to monotherapies are better tolerated by drug-sensitive glioma patients;[67] they prolong patient survival time and improve their quality of life.[68]

  Statins Top

Statins are common lipid-lowering drugs. They can inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which can effectively reduce cholesterol levels and reduce the risk of cardiovascular disease.[69] HMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway, and statins can affect the mevalonate pathway.[2] The mevalonate pathway is controlled by the p53 gene, which activates the expression of the ABCA1 gene.[70] The ABCA1 protein blocks the maturation of the sterol regulatory element-binding protein 2 protein, thereby inhibiting the mevalonate pathway.[70] The efficacy of various statins depends mainly on their affinity for HMG-CoA reductase. They competitively inhibit the activity of HMG-CoA reductase and prevent downstream product formation to affect cell signaling and apoptosis.[2],[70]

Damage to cellular DNA causes p53 to be activated and expressed and acts on the downstream p21 protein, which serves as a cyclin-dependent protein kinase inhibitor and binds to the cyclin–cyclin dependent kinase complex to inhibit the corresponding protein kinase activity.[71] Phosphorylated retinoblastoma proteins accumulate, preventing the E2F transcription factor from being activated and causing G1 phase arrest.[72] Studies have shown that statins regulate the activity of extracellular protein kinases and p38 proteins by regulating external signals and transmit signals to cells through the mitogen-AMPK signaling pathway, inducing the expression of related cytokines to inhibit cell growth.[73],[74] By regulating the mevalonate pathway, as HMG-CoA reductase inhibitors, statins cause tumor cell cycle arrest and apoptosis, thereby preventing the growth of tumors, such as gliomas.[75] For example, some studies have found that rosuvastatin can be used to treat glioma stem cells.[76],[77] Different concentrations of lovastatin have different inhibitory effects on glioma stem cells in a concentration-dependent manner and can reduce the expression of Bcl-2 gene.[78]

  Conclusion Top

These “old drugs” have been used clinically for many years, and their safety and feasibility are high. When using traditional antitumor drugs, possible combinations with these “old drugs” might enhance the therapeutic effect. Such combinations are expected to become a new strategy in chemotherapy for glioma in the clinic.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Maraka S, Groves MD, Mammoser AG, Melguizo-Gavilanes I, Conrad CA, Tremont-Lukats IW, et al. Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma. Cancer 2019;125:424-33.  Back to cited text no. 1
Moon SH, Huang CH, Houlihan SL, Regunath K, Freed-Pastor WA, Morris JP 4th, et al. p53 represses the mevalonate pathway to mediate tumor suppression. Cell 2019;176:564.  Back to cited text no. 2
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32:84-90.  Back to cited text no. 3
Armitage J. The safety of statins in clinical practice. Lancet 2007;370:1781-90.  Back to cited text no. 4
Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW. Non-steroidal anti-inflammatory drugs for chronic low back pain. Cochrane Database Syst Rev 2016;2:CD012087.  Back to cited text no. 5
Fan HW, Liu GY, Zhao CF, Li XF, Yang XY. Differential expression of COX-2 in osteoarthritis and rheumatoid arthritis. Genet Mol Res 2015;14:12872-9.  Back to cited text no. 6
Hiľovská L, Jendželovský R, Fedoročko P. Potency of non-steroidal anti-inflammatory drugs in chemotherapy. Mol Clin Oncol 2015;3:3-12.  Back to cited text no. 7
Igney FH, Krammer PH. Immune escape of tumors: Apoptosis resistance and tumor counterattack. J Leukoc Biol 2002;71:907-20.  Back to cited text no. 8
Green JS, Tsui BC. Impact of anesthesia for cancer surgery: Continuing professional development. Can J Anaesth 2013;60:1248-69.  Back to cited text no. 9
Khan YS, Gutiérrez-de-Terán H, Šqvist J. Molecular Mechanisms in the Selectivity of Nonsteroidal Anti-Inflammatory Drugs. Biochemistry 2018;57:1236-48.  Back to cited text no. 10
Igarashi Y, Chosa N, Sawada S, Kondo H, Yaegashi T, Ishisaki A. VEGF-C and TGF-β reciprocally regulate mesenchymal stem cell commitment to differentiation into lymphatic endothelial or osteoblastic phenotypes. Int J Mol Med 2016;37:1005-13.  Back to cited text no. 11
Yan XQ, Wang ZC, Li Z, Wang PF, Qiu HY, Chen LW, et al. Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9: Design, synthesis, inhibitory activity and 3D-QSAR analysis. Bioorg Med Chem Lett 2015;25:4664-71.  Back to cited text no. 12
Kesari S, Schiff D, Henson JW, Muzikansky A, Gigas DC, Doherty L, et al. Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol 2008;10:300-8.  Back to cited text no. 13
Somberg J, Molnar J. Sotalol versus amiodarone in treatment of atrial fibrillation. J Atr Fibrillation 2016;8:1359.  Back to cited text no. 14
Leanza L, Venturini E, Kadow S, Carpinteiro A, Gulbins E, Becker KA. Targeting a mitochondrial potassium channel to fight cancer. Cell Calcium 2015;58:131-8.  Back to cited text no. 15
Kelly DT. Verapamil in angina pectoris. Br J Clin Pharmacol 1986;21 Suppl 2:191S-5S.  Back to cited text no. 16
Turner KL, Sontheimer H. KCa3.1 modulates neuroblast migration along the rostral migratory stream (RMS) in vivo. Cereb Cortex 2014;24:2388-400.  Back to cited text no. 17
Urrego D, Tomczak AP, Zahed F, Stühmer W, Pardo LA. Potassium channels in cell cycle and cell proliferation. Philos Trans R Soc Lond B Biol Sci 2014;369:20130094.  Back to cited text no. 18
Ru Q, Tian X, Wu YX, Wu RH, Pi MS, Li CY. Voltage-gated and ATP-sensitive K+ channels are associated with cell proliferation and tumorigenesis of human glioma. Oncol Rep 2014;31:842-8.  Back to cited text no. 19
Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ. Exciting new advances in neuro-oncology: The avenue to a cure for malignant glioma. CA Cancer J Clin 2010;60:166-93.  Back to cited text no. 20
McFerrin MB, Sontheimer H. A role for ion channels in glioma cell invasion. Neuron Glia Biol 2006;2:39-49.  Back to cited text no. 21
Huang X, Jan LY. Targeting potassium channels in cancer. J Cell Biol 2014;206:151-62.  Back to cited text no. 22
Abe T, Mori T, Wakabayashi Y, Nakagawa M, Cole SP, Koike K, et al. Expression of multidrug resistance protein gene in patients with glioma after chemotherapy. J Neurooncol 1998;40:11-8.  Back to cited text no. 23
Piao YJ, Choi JS. Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats. J Pharm Pharmacol 2008;60:625-9.  Back to cited text no. 24
de Sant'Anna JR, Franco CC, Mathias PC, de Castro-Prado MA. Assessment of in vivo and in vitro genotoxicity of glibenclamide in eukaryotic cells. PLoS One 2015;10:e0120675.  Back to cited text no. 25
Bilir C, Engin H. Amiodarone and the risk of cancer: A nationwide population-based study. Cancer 2013;119:3578.  Back to cited text no. 26
Williams JB, Buchanan CG, Pitt WG. Co-delivery of doxorubicin and verapamil for treating multidrug resistant cancer cells. Pharm Nanotechnol 2018. doi: 10.2174/2211738506666180316122620.  Back to cited text no. 27
Jin Y, Bin ZQ, Qiang H, Liang C, Hua C, Jun D, et al. ABCG2 is related with the grade of glioma and resistance to mitoxantone, a chemotherapeutic drug for glioma. J Cancer Res Clin Oncol 2009;135:1369-76.  Back to cited text no. 28
Karla PK, Pal D, Mitra AK. Molecular evidence and functional expression of multidrug resistance associated protein (MRP) in rabbit corneal epithelial cells. Exp Eye Res 2007;84:53-60.  Back to cited text no. 29
Lou M, Zhao Y. Satisfactory therapy results of combining nimustine with nicardipine against glioma at advanced stage. J Cancer Res Ther 2015;11:1030.  Back to cited text no. 30
Brocker C, Vasiliou M, Carpenter S, Carpenter C, Zhang Y, Wang X, et al. Aldehyde dehydrogenase (ALDH) superfamily in plants: Gene nomenclature and comparative genomics. Planta 2013;237:189-210.  Back to cited text no. 31
Liu X, Wang L, Cui W, Yuan X, Lin L, Cao Q, et al. Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells. Oncotarget 2016;7:58516-30.  Back to cited text no. 32
Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol 2011;226:322-30.  Back to cited text no. 33
Akalay I, Janji B, Hasmim M, Noman MZ, André F, De Cremoux P, et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 2013;73:2418-27.  Back to cited text no. 34
Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci U S A 2013;110:8644-9.  Back to cited text no. 35
Huang CP, Tsai MF, Chang TH, Tang WC, Chen SY, Lai HH, et al. ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Lett 2013;328:144-51.  Back to cited text no. 36
Sládek NE, Kollander R, Sreerama L, Kiang DT. Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: A retrospective study. Rational individualization of oxazaphosphorine-based cancer chemotherapeutic regimens. Cancer Chemother Pharmacol 2002;49:309-21.  Back to cited text no. 37
Adam SA, Schnell O, Pöschl J, Eigenbrod S, Kretzschmar HA, Tonn JC, et al. ALDH1A1 is a marker of astrocytic differentiation during brain development and correlates with better survival in glioblastoma patients. Brain Pathol 2012;22:788-97.  Back to cited text no. 38
Lun X, Wells JC, Grinshtein N, King JC, Hao X, Dang NH, et al. Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clin Cancer Res 2016;22:3860-75.  Back to cited text no. 39
Rae C, Tesson M, Babich JW, Boyd M, Sorensen A, Mairs RJ. The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells. J Nucl Med 2013;54:953-60.  Back to cited text no. 40
Lee JH, Jeon SM, Hong SP, Cheon JH, Kim TI, Kim WH. Metformin use is associated with a decreased incidence of colorectal adenomas in diabetic patients with previous colorectal cancer. Dig Liver Dis 2012;44:1042-7.  Back to cited text no. 41
Hajjar J, Habra MA, Naing A. Metformin: An old drug with new potential. Expert Opin Investig Drugs 2013;22:1511-7.  Back to cited text no. 42
Hadad SM, Hardie DG, Appleyard V, Thompson AM. Effects of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. Clin Transl Oncol 2014;16:746-52.  Back to cited text no. 43
Sesen J, Dahan P, Scotland SJ, Saland E, Dang VT, Lemarié A, et al. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS One 2015;10:e0123721.  Back to cited text no. 44
Tseng CH. Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus. Aging (Albany NY) 2016;8:1636-49.  Back to cited text no. 45
Chen Z, Wang L, Chen Y. Antitumor mechanism of metformin via adenosine monophosphate-activated protein kinase (AMPK) activation. Zhongguo Fei Ai Za Zhi 2013;16:427-32.  Back to cited text no. 46
Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+metabolism and SIRT1 activity. Nature 2009;458:1056-60.  Back to cited text no. 47
Cai X, Hu X, Tan X, Cheng W, Wang Q, Chen X, et al. Metformin Induced AMPK Activation, G0/G1 Phase Cell Cycle Arrest and the Inhibition of Growth of Esophageal Squamous Cell Carcinomas in vitro and in vivo. PLoS One 2015;10:e0133349.  Back to cited text no. 48
Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006;441:424-30.  Back to cited text no. 49
Yi G, He Z, Zhou X, Xian L, Yuan T, Jia X, et al. Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. Int J Oncol 2013;43:1503-10.  Back to cited text no. 50
Yu Z, Zhao G, Li P, Li Y, Zhou G, Chen Y, et al. Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells. Oncol Lett 2016;11:2792-800.  Back to cited text no. 51
Lee JE, Lim JH, Hong YK, Yang SH. High-dose metformin plus temozolomide shows increased anti-tumor effects in glioblastoma in vitro and in vivo compared with monotherapy. Cancer Res Treat 2018;50:1331-42.  Back to cited text no. 52
Aldea MD, Petrushev B, Soritau O, Tomuleasa CI, Berindan-Neagoe I, Filip AG, et al. Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells. J BUON 2014;19:502-11.  Back to cited text no. 53
Yu Z, Zhao G, Xie G, Zhao L, Chen Y, Yu H, et al. Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cells in vitro and in vivo. Oncotarget 2015;6:32930-43.  Back to cited text no. 54
Gavrilov V, Lavrenkov K, Ariad S, Shany S. Sodium valproate, a histone deacetylase inhibitor, enhances the efficacy of vinorelbine-cisplatin-based chemoradiation in non-small cell lung cancer cells. Anticancer Res 2014;34:6565-72.  Back to cited text no. 55
Blaheta RA, Cinatl J Jr. Anti-tumor mechanisms of valproate: A novel role for an old drug. Med Res Rev 2002;22:492-511.  Back to cited text no. 56
Wang AD, Ji XY, Huang Q, Wang CR, Dong J, Lan Q. Studies on the target cells and molecules with sodium valproate induced differential of human glioma cells. Zhonghua Wai Ke Za Zhi 2007;45:1121-4.  Back to cited text no. 57
Liebelt BD, Shingu T, Zhou X, Ren J, Shin SA, Hu J. Glioma stem cells: Signaling, microenvironment, and therapy. Stem Cells Int 2016;2016:7849890.  Back to cited text no. 58
Ichiyama T, Okada K, Lipton JM, Matsubara T, Hayashi T, Furukawa S. Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. Brain Res 2000;857:246-51.  Back to cited text no. 59
Reichert JM, Dhimolea E. The future of antibodies as cancer drugs. Drug Discov Today 2012;17:954-63.  Back to cited text no. 60
Rampalli S, Pavithra L, Bhatt A, Kundu TK, Chattopadhyay S. Tumor suppressor SMAR1 mediates cyclin D1 repression by recruitment of the SIN3/histone deacetylase 1 complex. Mol Cell Biol 2005;25:8415-29.  Back to cited text no. 61
Zong H, Cao L, Ma C, Zhao J, Ming X, Shang M, et al. Association between the G870A polymorphism of Cyclin D1 gene and glioma risk. Tumour Biol 2014;35:8095-101.  Back to cited text no. 62
Janszky J, Tényi D, Bóné B. Valproate in the treatment of epilepsy and status epilepticus. Ideggyogy Sz 2017;70:258-64.  Back to cited text no. 63
Cinatl J Jr., Cinatl J, Driever PH, Kotchetkov R, Pouckova P, Kornhuber B, et al. Sodium valproate inhibits in vivo growth of human neuroblastoma cells. Anticancer Drugs 1997;8:958-63.  Back to cited text no. 64
Gupta A, Kumar A, Abrari A, Patir R, Vaishya S. Successful use of dose dense neoadjuvant chemotherapy and sodium valproate with minimal toxicity in an infant with medulloblastoma in extremely poor general condition. World Neurosurg 2016;93:485.e1-5.  Back to cited text no. 65
Ryu CH, Yoon WS, Park KY, Kim SM, Lim JY, Woo JS, et al. Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells. J Biomed Biotechnol 2012;2012:987495.  Back to cited text no. 66
Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, et al. A phase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. Int J Radiat Oncol Biol Phys 2015;92:986-92.  Back to cited text no. 67
Weller M, Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77:1156-64.  Back to cited text no. 68
Adam O, Laufs U. Rac1-mediated effects of HMG-CoA reductase inhibitors (statins) in cardiovascular disease. Antioxid Redox Signal 2014;20:1238-50.  Back to cited text no. 69
Joerger AC, Fersht AR. The p53 pathway: Origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem 2016;85:375-404.  Back to cited text no. 70
Li Y, Jenkins CW, Nichols MA, Xiong Y. Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. Oncogene 1994;9:2261-8.  Back to cited text no. 71
Gottifredi V, Karni-Schmidt O, Shieh SS, Prives C. p53 down-regulates CHK1 through p21 and the retinoblastoma protein. Mol Cell Biol 2001;21:1066-76.  Back to cited text no. 72
Altwairgi AK. Statins are potential anticancerous agents (review). Oncol Rep 2015;33:1019-39.  Back to cited text no. 73
Yano M, Matsumura T, Senokuchi T, Ishii N, Murata Y, Taketa K, et al. Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase ½ and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ Res 2007;100:1442-51.  Back to cited text no. 74
Tapia-Pérez JH, Kirches E, Mawrin C, Firsching R, Schneider T. Cytotoxic effect of different statins and thiazolidinediones on malignant glioma cells. Cancer Chemother Pharmacol 2011;67:1193-201.  Back to cited text no. 75
Liu M, Liu XP. Inhibitory effect of rosuvastatin on migration and invasion of U87 glioma cells in vitro. Zhongguo Bijiao Yixue Zazhi 2018;28:52-6.  Back to cited text no. 76
Liu M, Liu XP, Ding Q, Xu ZR. Effects of rosuvastatin on proliferation and apoptosis of human glioma U251 cells. Xiandai Yaowu yu Linchuang 2016;31:415-8.  Back to cited text no. 77
Afshordel S, Kern B, Clasohm J, König H, Priester M, Weissenberger J, et al. Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation – Impact of Ras-/Rho-prenylation. Pharmacol Res 2015;91:69-77.  Back to cited text no. 78

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