Open access peer-reviewed chapter

Drug Repositioning for the Treatment of Glioma: Current State and Future Perspective

Written By

Sho Tamai, Nozomi Hirai, Shabierjiang Jiapaer, Takuya Furuta and Mitsutoshi Nakada

Submitted: March 5th, 2020 Reviewed: May 12th, 2020 Published: July 14th, 2020

DOI: 10.5772/intechopen.92803

Chapter metrics overview

618 Chapter Downloads

View Full Metrics


Gliomas are the most common primary brain tumors. Among them, glioblastoma (GBM) possesses the most malignant phenotype. Despite the current standard therapy using an alkylating anticancer agent, temozolomide, most patients with GBM die within 2 years. Novel chemotherapeutic agents are urgently needed to improve the prognosis of GBM. One of the solutions, drug repositioning, which broadens the indications of existing drugs, has gained attention. Herein, we categorize candidate agents, which are newly identified as therapeutic drugs for malignant glioma into 10 classifications based on these original identifications. Some drugs are in clinical trials with hope. Additionally, the obstacles, which should be overcome in order to accomplish drug repositioning as an application for GBM and the future perspectives, have been discussed.


  • glioma
  • glioblastoma
  • drug repositioning
  • chemotherapy
  • temozolomide
  • existing drugs
  • pre-drugs

1. Introduction

Many diseases require the development of new drugs for effective treatment. The relevance of drug repurposing in medical science has progressively grown recently. The increasing interest in drug repurposing is realized based on the increase of related academic publications.

Annually, approximately 23 per 100,000 people suffer from tumors of the central nervous system (CNS). Gliomas, which account for 25% of all CNS tumors, are the most common primary brain tumors, and most are malignant [1]. Glioblastoma (GBM) is a malignant glioma with the worst prognosis, as it accounts for 60% of all gliomas and is classified as grade IV by the World Health Organization (WHO) [1, 2]. Despite aggressive therapies, the median overall survival (OS) of patients who suffer from GBM is only 15–18 months [1, 3].

The current treatments for GBM are maximum surgical resection and adjuvant chemoradiotherapy. The first-line agent for chemotherapy is temozolomide (TMZ), an imidazotetrazinone derivative [4]. TMZ acts as a major groove-directed deoxyribonucleic acid (DNA)-alkylating agent, and its molecular weight is only 194 Da [4]. A phase III clinical trial revealed that concomitant and adjuvant TMZ with radiotherapy is effective for the treatment of patients with primary GBM [5]. Approximately half of the cases of GBM have a methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter, and these cases are associated with a favorable outcome after concomitant and adjuvant TMZ with radiotherapy [6]. MGMT potentially removes methyl adducts at the O6 position of guanine and indicates resistance to alkylating agents; however, the methylation of the MGMT promoter interferes with MGMT activity and induces glioma cell death [6].

Clinical trials have revealed the therapeutic benefit of bevacizumab (BEV), a recombinant, humanized, monoclonal antibody against vascular endothelial growth factor (VEGF), in patients with cancer [7]. Large-scale clinical studies have been performed to investigate the therapeutic effects of BEV in patients with newly diagnosed GBM [8, 9]. However, the clinical benefits of BEV in patients with glioma are still unknown.

Research into drug repositioning for GBM is now expanding, although no effective drug has yet been reported with strong and solid evidence. Herein, we focus on candidate agents with therapeutic effects in malignant glioma and that have undergone clinical trials to evaluate their efficacy in patients. We also describe the issues of drug repositioning in malignant glioma.


2. Current candidate agents for glioma

Here, we categorize candidate agents into 10 classifications (Table 1).

Candidate agentOriginal indication diseaseMechanism of original diseaseMechanism of anti-glioma effectCTRefs.
2.1 Antidiabetic drugs2.1.1 MetforminDiabetes mellitusSuppress gluconeogenesis in the liverActivate AMPK
Inhibit glutamate dehydrogenase
NY[10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20]
2.2 Antihypertensive drugs2.2.1 Angiotensin II receptor blockerHypertensionBlock angiotensin II receptorInhibit vascular endothelial growth factorIII[21, 22, 23, 24, 25]
2.2.2 β-blockerHypertensionBlock β receptorDecrease cAMP levelsNY[26, 27]
2.2.3 Calcium channel blockerHypertensionBlock calcium channelInhibit hippo pathwayNY[28, 29]
2.3 Antiepileptic drugs2.3.1 Valproic acidEpilepsyBlock sodium channelInhibit GSK3βNY[31, 32, 33, 34, 35, 36, 37, 38, 39]
2.3.2 LevetiracetamEpilepsyBlock calcium channelInhibit MGMT expressionII[40, 41]
2.4 Pesticides2.4.1 ChloroquineMalaria (Plasmodiumspp.)Inhibit heme polymerizationInhibit TGF-β and NF-κBII[42, 43, 44, 45, 46]
2.4.2 PentamidinePneumocystis pneumoniaInhibition of glucose metabolism, protein synthesis, amino acid transport and ribonucleic acid synthesisUnknownNY[47, 48, 49]
2.5 Antipsychotic drugs2.5.1 FluvoxamineDepressionSelective serotonin reuptake inhibitorSuppress the activity of actin polymerization regulatorsNY[50, 51, 52, 53, 54, 55, 56, 57]
2.5.2 FluspirileneSchizophreniaDephenylbutylpiperidineInhibit activation of STAT3NY[58, 59, 60, 61, 62]
2.6 Antineoplastic drugs2.6.1 EribulinBreast cancerInhibit of microtubule activityInhibitor of telomerase reverse transcriptase- RNA-dependentII[63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76]
2.7 Anti-inflammatory drugs2.7.1 Acetylsalicylic acid drugsFever, inflammation diseaseInhibit cyclooxygenaseActivate connexin 43, suppress Wnt/β-catenin/T-cell factor signaling and SHH/GLI1 pathwayNY[77, 78, 79, 80, 81]
2.7.2 SulfasalazineRheumatoid arthritisBlock activation of NF-κBBlock activation of NF-κBI/II[82, 83, 84, 85, 86]
2.8 Multiple drug combination therapy2.8.1 CLOVA cocktailInhibit GSK3βI/II[87, 88, 89, 90]
2.8.2 CUSP9* treatmentSuppress multiple molecule pathwayNY[91, 92]
2.8.3 FTT cocktailInhibit ROCK2/moesin/β-catenin pathway, suppress TGF-βNY[93, 94, 95, 96]
2.9 Other drugs2.9.1 DisulfiramAlcoholismInhibitor of ALDHInhibiting polo-like kinese-1II[97, 98, 99, 100, 101]
2.9.2 StatinsDyslipidemiaInhibited 3-hydroxy-3-methylglutaryl-coenzyme A reductaseActivate transcription factor-2 and c-jun, suppress ERKNY[102, 103, 104, 105, 106]
2.10 Pre drugs2.10.1 Kenpaullone--Inhibit GSK3βNY[107, 108, 109, 110, 111]
2.10.2 2-Fluoropalmitic acid--Dephosphorylate ERK, suppress MMP-2NY[112, 113, 114, 115]

Table 1.

The list of candidate agents.

ALDH, aldehyde dehydrogenase; AMPK, AMP-activated protein kinase; CT, clinical trial; ERK, extracellular signal-regulated kinase; GLI1, glioma-associated oncogene homolog 1; GSK3β, glycogen synthase kinase 3β; MGMT, O6-methylguanine-DNA methyltransferase; MMP-2, matrix metalloproteinase-2; NF-κB, nuclear factor- kappaB; NY, not yet; ROCK2, Rho-associated protein kinase 2; SHH, sonic hedgehog; STAT3, signal transducer and activator of transcription 3; TGF-β, tumor growth factor-β.

2.1 Antidiabetic drugs

2.1.1 Metformin

The intracellular metabolic pathway of cancer cells differs from that of normal cells, as represented by the Warburg effect, and is considered as a cancer therapeutic target. Metformin is a biguanide antidiabetic drug that exerts a hypoglycemic effect via the suppression of gluconeogenesis in the liver and promotion of glucose uptake in the muscle and adipose tissues. The antitumor effects of metformin are widely known and reported in various cancers, such as breast cancer [10].

Basic research with metformin in glioma cells and glioma stem-like cells (GSCs) has shown that metformin targets multiple pathways (Figure 1). Metformin activates AMP-activated protein kinase (AMPK) via the inhibition of oxidative phosphorylation in mitochondrial complex I, which increases the AMP/ATP ratio, thereby inhibiting the mammalian target of rapamycin (mTOR) and promoting apoptosis [11, 12]. The metformin-mediated activation of AMPK, followed by the activation of forkhead box O3 (FOXO3), induces GSC differentiation and reduces tumorigenicity [13]. The Cancer Genome Atlas has reported missense mutations in isocitrate dehydrogenase (IDH) genes 1 and 2. D-2-Hydroxyglutarate (D-2HG), a cancer metabolite produced by the mutant IDH protein, contributes to the development and progression of cancer. The conversion of glutamine to α-ketoglutarate (αKG) is catalyzed by glutamate dehydrogenase (GDH), and the inhibition of GDH by metformin reduces the production of D-2HG in glioma with the IDH 1/2 mutation [14]. Chloride intracellular channel 1 (CLIC1) is involved in the progression of various cancers, including GBM [15, 16, 17]. CLIC1 is involved in the regulation of the G1/S transition, and metformin causes G1 cell cycle arrest in GSCs by the selective inhibition of CLIC1 [18].

Figure 1.

Antitumor mechanisms of metformin in glioma. The inhibition of oxidative phosphorylation in mitochondrial complex I induces the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and activation of FOXO3 via activating AMPK. The inhibition of GDH reduces the D-2HG production via αKG reduction in IDH 1/2 mutation glioma. Selective inhibition of CLIC1 causes G1 cell cycle arrest in GSCs.

An epidemiological study using the Clinical Practice Research Datalink reported that the use of metformin is not associated with a reduced risk of glioma [19]. In a pooled analysis that included 1731 patients from large-scale randomized controlled trials, the use of metformin was not significantly associated with OS or progression-free survival (PFS) in patients with newly diagnosed GBM [20]. Although the results of existing retrospective and epidemiological studies are somewhat discouraging, randomized clinical trials are underway, and we expect to see encouraging results in the future.

2.2 Antihypertensive drugs

2.2.1 Angiotensin II (AT2) receptor blocker

AT2 plays a major role in the renin-angiotensin-aldosterone system and regulates vascular homeostasis, mainly via the activation of angiotensin I receptor (AT1R) and AT2 receptor. Recent studies have revealed that AT2 has roles in cell proliferation, differentiation, apoptosis, and migration. Furthermore, AT2 induces angiogenesis via the stimulation of growth factors such as VEGF, which suggests that AT2 is a target for cancer therapy [21, 22]. Rivera et al. first reported the presence of AT1R in glioma cells and demonstrated that the selective blockade of AT1R with losartan in C6 glioma rats exerts antitumor effects via the inhibition of tumor growth and angiogenesis [22]. The group also showed that treatment with losartan inhibits tumor growth via the inhibition of VEGF and promotes apoptosis in vitro and in vivo [23]. A retrospective analysis of 81 patients with newly diagnosed GBM showed that the administration of an AT2R blocker or angiotensin-converting enzyme (ACE) inhibitor with the current treatment is associated with reduced brain edema and steroid requirements and improved clinical outcomes [24]. Nevertheless, the ASTER trial (NCT01805453), a randomized, placebo-controlled trial, which included losartan to the current treatment for patients with GBM, did not show any difference in steroid requirements or a significant increase in the median OS [25].

2.2.2 β-Blocker

Tewarie et al. summarized previous preclinical and clinical studies about the effects of β-blockers on gliomas and noted reduced cell proliferation via a decrease in cAMP levels, time-dependent cell cycle arrest, and reduced cell migration [26]. However, in a retrospective cohort study of 218 patients with recurrent GBM, Johansen et al. observed no correlation between the usage of β-blockers and OS and PFS [27].

2.2.3 Calcium channel blocker

The altered expression and activity of specific Ca2+ channels and pumps have been reported in malignant gliomas [28]. Amlodipine, a commonly used antihypertensive drug, was shown to inhibit tumor growth by the inhibition of YAP/TAZ signaling via the hippo pathway, which is involved in tumor malignancy by the activation of store-operated Ca2+ entry. This allows intracellular Ca2+ influx [29]. Most research on calcium signaling in GBM is recent and further study is warranted.

2.3 Antiepileptic drugs

A common symptom of GBM is epilepsy, which occurs in half of all cases; thus, patients are often treated with antiepileptic drugs, such as valproic acid (VPA) and levetiracetam (LEV) (Figure 2). Enzymatic modifications of histone proteins that regulate gene expression have been investigated as therapeutic drug targets. Histones are modified by histone acetyltransferase (HAT) and histone deacetylase (HDAC). A HDAC inhibitor (HDACi) enhances the acetylation by HAT and causes a hyperacetylated state, which exerts multiple antitumor effects such as cell differentiation, apoptosis, cell cycle arrest, sensitivity to chemotherapy, and inhibition of migration and angiogenesis [30].

Figure 2.

Antitumor mechanisms of VPA and LEV in glioma.VPA:hyperacetylation of histones via the inhibition of HDAC suppresses cell proliferation and increases radiosensitivity. The activation of Akt/extracellular signal-regulated kinase (ERK) inhibits glycogen synthase kinase-3β (GSK3β) and induces apoptosis.LEV:recruitment of the mSin3A/HDAC1 corepressor complex and direct binding to the MGMT promoter via p53. Abbreviations: HAT, histone acetyltransferase; MEK, mitogen-activated protein kinase/ERK kinase; PI3K, phosphoinositide 3-kinase; TMZ, temozolomide.

2.3.1 Valproic acid

Recently, VPA has been shown to be an effective HDACi and has been proposed as a drug for cancer treatment [31]. VPA inhibits the proliferation of glioma cells and enhances radiosensitivity by increasing hyperacetylation in vitro and in vivo [32]. Another antitumor effect of VPA is the induction of apoptosis by the inhibition of GSK3β via the activation of Akt/ERK [33]. According to several studies, the inhibition of GSK3β suppresses survival and proliferation and induces apoptosis in human GBM cells [34]. However, some meta-analyses have revealed that the clinical benefit of VPA combination treatment in patients with GBM was contraindicated [35, 36, 37, 38, 39], and further studies are warranted.

2.3.2 Levetiracetam

LEV has been shown to increase HDAC1 transcription, recruit the mSin3A/HDAC1 corepressor complex on the MGMT promoter, and inhibit MGMT expression through the direct binding of p53 to the MGMT promoter [40]. Thus, LEV inhibits glioma cell proliferation and significantly potentiates the cytotoxic effects of TMZ in glioma cells and GSCs [40, 41]. A phase II clinical trial (NCT02815410) is ongoing and the results are expected in the future.

2.4 Pesticides

2.4.1 Chloroquine (CHQ)

CHQ is a therapeutic drug for the treatment of malaria [42]. This agent has antitumor effects for some cancer cells, including glioma cells [43]. However, the mechanism of the antitumor effect of CHQ in glioma is not well known. Some studies have suggested that CHQ leads to cancer cell death by controlling autophagy [44], and recent research has revealed more effects of CHQ treatment. CHQ adjusts the metabolism of amino acids and inhibits glycogenesis [42]. CHQ administration also induces the alteration of mitochondrial membrane potential in glioma cells and causes apoptosis [45]. Some studies have investigated the molecular signaling associated with CHQ treatment. The molecular signaling changes in glioma cells caused by CHQ include the inhibition of the signaling pathway of transforming growth factor-β (TGF-β) and nuclear factor-kappaB (NF-κB), which play a role in tumorigenesis [42, 45]. CHQ treatment also suppresses glioma cell invasion by the inhibition of matrix metalloproteinase-2 (MMP-2) and improved radiosensitivity by the accumulation of glioma cells in the G2/M phase [45]. Based on the results of these in vitro studies, clinical trials that investigated the therapeutic effects of CHQ in patients with glioma have been conducted [43]. In a randomized trial (double-blind, placebo-controlled) of patients with primary GBM, there were no statistically significant differences between the CHQ treatment group and the placebo group; however, the death rate in the CHQ group was half as large as that in the placebo group [46]. Further clinical trials are in progress (NCT03243461, NCT02432417, and NCT02378532).

2.4.2 Pentamidine

Pentamidine is effective in the treatment of pneumonia caused by Pneumocystis jirovecii. This drug exerts its therapeutic effects via the inhibition of glucose metabolism, protein synthesis, amino acid transport, and ribonucleic acid (RNA) synthesis [47]. Previous studies have shown the therapeutic effects of pentamidine in various cancers [48]. One in vitro study revealed that pentamidine suppressed cancer activity via the inhibition of phosphatase of regenerating liver (PRL) [48] and the inhibition of PRL phosphatase suppressed the activation of Akt and ERK [49]. Based on these studies, we investigated the effect of pentamidine in glioma cells and GSCs. Pentamidine suppressed the proliferation of glioma cells and GSCs and reduced the stemness of GSCs. Additionally, there are clinical benefits to repurposing pentamidine as the therapeutic drug for malignant glioma, because the current chemoradiotherapy sometimes induces lymphopenia as a side effect and patients might suffer from pneumonia caused by P. jirovecii. Further research to investigate the molecular mechanism of pentamidine is in underway. In the future, clinical trials are warranted to determine the benefit of pentamidine for patients with malignant glioma.

2.5 Antipsychotic drugs

2.5.1 Fluvoxamine

Fluvoxamine has been used as an antidepressant since 1986 and is widely applied in the treatment of anxiety disorders owing to its selective serotonin reuptake inhibitor activity, which helps maintain sufficient serotonin levels in the brain to function [50, 51]. Recently, a new screening method for the quantitative determination of actin polymerization showed that fluvoxamine inhibits the formation of F-actin, which induces lamellipodial protrusions, focal adhesions, and stress fibers at the edge of GBM and is essential for the migration and invasion of GBM cells into normal brain tissues [52, 53, 54]. The molecular signal changes in fluvoxamine-treated glioma cells are achieved by the suppression of the activity of actin polymerization regulators, focal adhesion kinases, and mTOR complex 2 [55, 56]. The daily administration of fluvoxamine to an intracranial xenograft mouse model significantly prolongs survival and blocks the infiltration of tumor cells into normal brain tissues in vivo [57]. Therefore, fluvoxamine disrupts focal adhesion and actin depolymerization, blocks the migration and invasion ability of GBM cells, and prolongs patient survival. Fluvoxamine is a potentially effective anti-invasive drug for the treatment of glioma.

2.5.2 Fluspirilene

Fluspirilene, a member of the diphenylbutylpiperidine class of drugs, is an effective, traditional, long-acting antipsychotic [58, 59]. Fluspirilene displays an effective Ca2+ channel blocking activity [60] and inhibits synaptic transmission; thus, fluspirilene can mitigate a seizure [58]. However, recent studies have shown a new effect of fluspirilene against some incurable cancers, such as hepatocellular carcinoma [61] and GBM [62]. Fluspirilene has been identified as a potential anti-GSC drug. An in vitro investigation has shown that fluspirilene not only attenuates the cell viability, stemness, sphere-forming ability, and proliferation of GSCs but also suppresses the invasion of GBM cells via the inhibition of signal transducer and activator of transcription 3 (STAT3) activity and its nuclear reduction in GBM cells [62]. In vivo, fluspirilene significantly decreases tumor volume and prolongs survival in an intracranial xenograft mouse model [62]. These results suggest that fluspirilene is a potential novel anti-glioma candidate.

2.6 Antineoplastic drugs

2.6.1 Eribulin

Eribulin, a non-taxane inhibitor of microtubule dynamics [63, 64], was approved by the US Food and Drug Administration (FDA) in 2010 for the treatment of stage 4 breast cancer [65]. Eribulin prevents the growth of tumor cells via the inhibition of microtubule activity during cell mitosis and induces M-phase arrest, which result in cell apoptosis (Figure 3) [66, 67]. Eribulin also reduces the aberrance of the vascular microenvironment of a tumor [68]. Based on these effects on various cancers, recent studies have demonstrated that eribulin sensitizes a tumor to radiation via eribulin-induced M-phase arrest and causes more DNA damage than radiation alone. This induces an increase in cleaved caspase-3 and cleaved poly-ADP ribose polymerase levels and results in mitotic catastrophe (Figure 3) [69, 70]. An in vivo study of the concomitant administration of radiation with eribulin showed that this combination prolongs the survival of the intracranial xenograft GBM mouse model [71]. Eribulin also suppresses vascular remodeling and normalizes the radiation-induced aberrant vascular microenvironment in the xenograft mouse model [71]. A growing evidence indicates that a telomerase reverse transcriptase (TERT) promoter mutation, a common mutation in GBM [72], maintains telomerase activity to evade telomere shortening; thus, tumor cells overcome replicative senescence and proliferate infinitely [73] telomerase-independent RNA-dependent RNA polymerase (RdRP) activity [74, 75]. Eribulin has been identified as a specific inhibitor of TERT-RdRP through drug screening [76]. Thus, TERT-targeting therapies would be a novel direction to treat glioma (Figure 3). Both in vitro and in vivo experiments using eribulin to treat gliomas have shown that eribulin exerts an anticancer activity and suppresses glioma proliferation through its function as a TERT-RdRP inhibitor, in addition to its microtubule inhibitor activity. Now, eribulin is in a phase II doctor-led clinical trial in recurrent GBM (UMIN ID: 000030359).

Figure 3.

Antitumor mechanisms of eribulin. The effect of eribulin against glioblastoma multiforme. Eribulin suppresses microtubule activity and induces M-phase arrest, which makes cells more radiosensitive and ends up with apoptosis. Eribulin also suppresses proliferation by inhibiting the TERT-RdRP activity.

2.7 Anti-inflammatory drugs

2.7.1 Acetylsalicylic acid (ASA)

ASA, a nonsteroidal anti-inflammatory drug, is used worldwide. Previous studies have shown the molecular signaling changes by aspirin (Figure 4). ASA exerts an anticancer via the inhibition of prostaglandin, including prostaglandin E2 (PGE2), synthesis through the acetylation, and inhibition of cyclooxygenase [77, 78]. ASA treatment suppresses the invasion of glioma cells via the activation of the expression of connexin 43 (Cx43), which is a major gap junction protein in astrocytes. Cx43 is normally suppressed by PGE2. Thus, ASA-treated glioma cells would overexpress Cx43 and the invasion would be inhibited [79]. Other studies have revealed that ASA suppresses the Wnt/β-catenin/T-cell factor (TCF) signaling pathway, which plays a key role in glioma progression [79]. Wnt/β-catenin/TCF pathway suppression would suppress glioma via the regulation of downstream genes, c-mycand cyclin D1. ASA inhibits the sonic hedgehog (SHH)/glioma-associated oncogene homolog 1 (GLI1) pathway and adjusts the epithelial-to-mesenchymal transition [80]. The SHH/GLI1 pathway is also associated with recovery from the damage by TMZ [80]. Based on these studies, a retrospective cohort study was performed to investigate the therapeutic effect of ASA in patients with malignant glioma. The results revealed that the use of ASA is associated with a higher OS and PFS in patients with WHO grade III glioma; however, there was no difference in OS and PFS in patients with WHO grade IV glioma [81]. In the future, prospective multicenter randomized studies are warranted to determine the effect of ASA in malignant glioma.

Figure 4.

Antitumor mechanisms of acetylsalicylic acid. ASA indicates multimodal effects for glioma cells. ASA suppresses the invasion of glioma cells by activating the expression of connexin 43. ASA also suppressesc-mycandcyclin D1through Wnt/β-catenin/TCF pathway and interfered the recovery of DNA damages and adjusted the epithelial-to-mesenchymal transition through SHH/GLI1 pathway. Abbreviation: PGE2, prostaglandin E2.

2.7.2 Sulfasalazine (SAS)

SAS, which is approved for the treatment of rheumatoid arthritis and inflammatory bowel diseases, may be a therapeutic drug for malignant glioma [82]. SAS exerts anti-inflammatory effects by blocking the activation of NF-κB and the Xc antiporter system, which usually causes the uptake of cystine, release of glutamate, and increase in the levels of reactive oxygen species (ROS) [83]. NF-κB is activated in GBM tissues and promotes cell proliferation and survival. SAS blocks the cell cycle and induces apoptosis in vitro and inhibits the growth of brain tumors in mouse xenograft models [83, 84]. However, a phase I/II study of the current therapy with SAS for patients with recurrent malignant glioma showed no clinical benefit of SAS [85]. Recently, a phase I/II study of the current therapy with SAS in patients who were newly diagnosed GBM was performed [86], which showed that there is no increase in OS and PFS in the current therapy with SAS group compared to the current therapy group. Results suggest that this new regimen would improve seizure control; however, the therapeutic effect of SAS would be limited.

2.8 Multiple-drug combination therapy

A combination therapy with different drugs targeting on multiple molecules that contribute to malignancy is rational and enhances antitumor effects, reduces side effects, and avoids resistance. This section provides an overview of the treatment of recurrent GBM with multiple existing drugs (Figure 5).

Figure 5.

Multiple molecular-targeted therapies by multiple-drug treatment with temozolomide. Multiple existing drug combination, CLOVA cocktail, CUSP9* treatment, and FTT cocktail, targets multiple signaling pathways which attribute GBM malignant phenotype. Abbreviations: 5-LO, 5-lipoxygenase; ABCG2, ATP-binding cassette super-family G member 2; ACE, angiotensin-converting enzyme; ALDH, aldehyde dehydrogenase; AMPK, adenosine monophosphate; CA, carbonic anhydrase; CDK, cyclin-dependent kinase; COX, cyclooxygenase; FAK, focal adhesion kinase; GSK3β, glycogen synthase kinase-3β; HDAC, histone deacetylase; HH, hedgehog; JNK, c-Jun N-terminal kinase; MGMT, O6-methylguanine-DNA methyltransferase; MMP, matrix metalloproteinase; MT, membrane type; mTOR, mammalian target of rapamycin; NK-1, neurokinin-1; NF-κB, nuclear factor-kappaB; P-gp, P-glycoprotein; ROCK, rho-associated protein kinase; ROS, reactive oxygen species; TCTP, translationally controlled tumor protein; TF, tissue factor; TGF-β, transforming growth factor-β; TMZ, temozolomide; VEGF, vascular endothelial growth factor.

2.8.1 CLOVA cocktail

The CLOVA cocktail, composed of cimetidine, lithium, olanzapine, and valproate, targets dysregulated GSK3β in GBM [87, 88, 89]. The therapeutic effects of GSK3β inhibition are the suppression of tumor cell survival and proliferation, synergy with TMZ and irradiation, attenuation of invasion, and induction of GSC differentiation via various pathways [90]. Olanzapine stimulates AMPK catabolic action, followed by the induction of p53-dependent autophagy. VPA, as an HDACi, enhances the effect of radiation. A phase I/II clinical study to investigate the efficacy and safety of the CLOVA cocktail in patients with TMZ-resistant recurrent GBM revealed that this regimen is well tolerated and results in a higher OS than the control group treated with TMZ alone [87].

2.8.2 CUSP9* treatment

The rational of the coordinated undermining of the survival paths active in GBM by nine repurposed drugs [aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram (DSF), itraconazole, ritonavir, and sertraline], termed CUSP9*, was developed to prevent therapeutic resistance in tumor cells. CUSP9* targets the diverse complementary redundant pathways to render tumor cells susceptible to the cytotoxic effects of TMZ [91] by the simultaneous administration of nine drugs with low-dose daily TMZ. Each drug exerts different inhibitory effects on the 17 molecules and pathways shown in Figure 5. Auranofin and DSF increase the level of intracellular reactive oxygen species [96]. Recently, the experimental CUSP9* strategy with TMZ was shown to suppress the stemness of GSCs and tumorigenesis via the blockade of the Wnt/β-catenin pathway [92].

2.8.3 FTT cocktail

A unique therapeutic approach to reprogram and reverse cancer cells to normal somatic cells has attracted attention. The combination of fasudil, tranilast, and TMZ was identified to reprogram GBM cells into neuronal like cells [93]. GBM cells treated with the FTT cocktail show normal neuronal morphology, gene expression, and electrophysiological properties and lower malignancy than untreated cells. This might be caused by the synergistic effect of the three drugs [93]. In addition, the FTT cocktail suppresses tumor growth and prolongs survival in a GBM xenograft model more than TMZ alone. Fasudil inhibits the ROCK2/moesin/β-catenin pathway in TMZ-resistant glioma cell lines and downregulates the ATP-binding cassette super-family G member 2 transporter to increase sensitivity to TMZ [94]. The inhibition of ROCK with mTOR inhibition exerts neuronal reprogramming more effectively in vitro and in vivo than the inhibition of ROCK alone [95], which suggests the possibility of more drug combinations. Tranilast alone inhibits glioma progression via TGF-β restriction [96]. Although the mechanism underlying the tumor-suppressive function of the FTT cocktail is not fully elucidated, this cocktail might improve the current therapy for malignant glioma.

2.9 Other drugs

2.9.1 Disulfiram

DSF, the FDA-approved drug for the treatment of alcohol abuse, may be a therapeutic drug for GBM. DSF is an irreversible inhibitor of aldehyde dehydrogenase [97], which is a functional marker of cancer stem cells [98]. An in vitro study revealed that DSF is an inhibitor of MGMT and enhances the efficacy of alkylator-induced tumor death [99]. Another study revealed that DSF suppresses the growth and self-renewal of GSCs via the inhibition of polo-like kinase-1, which controls cell progression and cytokinesis [97]. The activity of DSF is potentiated by copper and induces GSC death [100]. However, an open-label, single-arm phase II study of TMZ plus DSF for patients with recurrent TMZ-resistant GBM showed that the objective response rate is 0% and DSF combination therapy would have only limited therapeutic effects for patients with GBM [101].

2.9.2 Statins

Statins, a therapeutic drug for dyslipidemia, inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Some statins have a therapeutic effect on glioma cells [102, 103]. In vitro, simvastatin induces the apoptosis of C6 glioma cells by phosphorylation of activating transcription factor-2 and c-Jun [102]. Lovastatin suppresses the proliferation and migration of glioma cell lines via the suppression of the activation of ERK [103]. A retrospective cohort study suggested that the long-term prediagnostic statin intake increases the OS in patients with GBM [104]. Another retrospective cohort study suggested that statin intake is associated with fewer seizures in patients with GBM [105]. However, other cohort studies have not indicated a survival relationship between malignant glioma and statin intake. Finally, a meta-analysis of these retrospective cohort studies revealed that statins do not increase the PFS and OS in patients with GBM [106]. In the future, prospective multicenter randomized studies are warranted to determine the effect of statins in malignant glioma.

2.10 Pre-drugs

2.10.1 Kenpaullone

Kenpaullone, a potent and nonselective inhibitor of GSK3 [107], is a serine/threonine kinase that regulates numerous signaling pathways involved in cell cycle control, proliferation, differentiation, and apoptosis [108, 109]. Kenpaullone treatment inhibits glioma cell proliferation, suppresses anti-apoptotic mechanisms in the mitochondria, inhibits pro-survival factors, and attenuates the stemness and viability of GSCs via the downregulated activity of GSK3β [88, 110, 111]. The combination of low-dose kenpaullone with TMZ enhances cytotoxicity against glioma via the induction of c-Myc-mediated apoptosis [110]. These results suggest that kenpaullone is a potential compound for the treatment of glioma.

2.10.2 2-Fluoropalmitic acid (2-FPA)

Recently, 2-FPA, a new fatty acid inhibitor compound, has been identified as a potential anti-glioma agent through a drug screening system for drugs that target cancer stem cells using existing drug libraries [62]. As an active chemical compound, the safety of 2-FPA for normal brain cells has not yet been revealed. There are no reports that have mentioned the effect of 2-FPA in other cancers. An in vitro investigation using GSCs and GBM cells [112] has shown that 2-FPA suppresses the viability and sphere-forming ability of GSCs; inhibits the proliferation of GBM cells via the dephosphorylation of ERK, which is essential for the proliferation and invasion of glioma [113]; and blocks the invasion of GBM cells via the suppression of the activity of MMP-2, which plays an important role in cell invasion [114]. In addition to its mono activity against glioma, the combination of 2-FPA with TMZ synergistically enhances the efficacy of TMZ against glioma in vitro via the increase in MGMT promoter methylation and downregulation of MGMT, the main and predominant reasons for TMZ resistance [115], which suggest that combination therapy may be one strategy to improve TMZ efficacy and overcome resistance. Overall, 2-FPA is a potential therapeutic agent against GBM. To extend these results, physiological studies are required.


3. Issues of drug repositioning for glioma

Despite these studies, some problems remain in drug repositioning for the treatment of glioma because of the uniqueness of this brain tumor.

The biggest problem is the penetration of the blood-brain barrier (BBB), which restricts the passage of molecules, including candidate agents. The BBB is a multilayered barrier between the blood and brain tissues to regulate the environment of the brain. The BBB has a good permeability for nutrients that are required for nerve cells [116]. Additionally, the BBB adjusts the ionic composition and the concentration of neurotransmitters, such as neuroexcitatory amino acids, to maintain the optimal environment for synapses. If ions and neurotransmitters spread into the CNS in an uncontrolled manner, the synapse is insufficiently stimulated and brain tissue is damaged [116]. The BBB also prevents the penetration of macromolecules more than 400–500 Da to exclude neurotoxic molecules [117]. Some plasma proteins induce the apoptosis of nerve cells [116]. This multilayered barrier blocks these proteins and would block the penetration of candidate agents. To overcome this problem, techniques are being explored. Some studies have investigated a new drug delivery system that uses an ultrasound-sensitizing nanoparticle complex, as preliminary studies have revealed that an ultrasound with microbubbles could open the BBB locally [118]. Other studies have evaluated the usefulness of convention-enhanced delivery therapy, which is a local infusion therapeutic technique to directly introduce a drug to brain neoplasms [119, 120].

A malignant glioma has features that are different from those in other malignant tumors. First, a malignant glioma has heterogeneity. Some malignant cancers, such as acute leukemia, are homogeneous; thus, the appropriate candidate agent would induce remission because “the weak point” of all tumor cells is the same. However, a malignant glioma is a complicated aggregation, once called “glioblastoma multiforme” [121]. If one candidate agent exerts therapeutic effects for some glioma cells, other resistant glioma cells would multiply. To overcome this problem, several previous studies have performed multiple-drug combination therapy. This therapy would focus on multiple therapeutic targets at once with minimal side effects [85]; however, currently, there are no combination treatments that can replace the current treatments. Second, despite its clinical aggressiveness, 60–70% of the tumor cells in malignant glioma are in the nonproliferating phase [122]. This indicates that not only heterogeneous cells but also the cell cycle must be considered because resting cells indicate resistance to chemoradiotherapy [122]. Based on this, some studies have focused on candidate agents that can change the phase of the cell cycle [18, 45].


4. Perspective

The strategy to discover the most effective drug is the key to accomplish a successful drug repositioning. One of the main methods is an in vitro or in vivo drug screening system in which target cells are treated by various existing drugs and the alteration to the malignant phenotype, such as by cytotoxicity, is analyzed. Drugs that exert cytotoxicity in GBM cells, especially GSCs, at low concentrations would be good candidates. Since the previous reports mention that GSCs were the cause of recurrence of GBM [100], GSCs can be good target. Lower drug concentration can minimize side effects. However, to achieve this strategy, appropriate experimental resources, including candidate agents, drug screening systems, and established cell lines are required. Epidemiological discovery is another option, such as the measurement of the incidence of a certain disease in the population to which specific drugs are administered. Serendipity is an important factor in this strategy. For instance, a prospective cohort study revealed a lower cancer incidence in people with schizophrenia [123]. This led us to the idea that antipsychotic drugs possess therapeutic effects against cancers including glioma [57, 62]. However, the most efficient method might be mutual molecular and structure analyses between target cells and drugs using artificial intelligence (AI). Different biochemical and mathematical techniques have been designed and optimized to accurately infer links between target cells and drugs. Drug-target interaction prediction is an important part of most rational drug repositioning pipelines. The major target molecules for malignant glioma are Akt, ERK, and STAT3, which sustain malignant phenotype [62, 103, 113].

The supply of research resources is also important. Pharmaceutical companies hold the materials for drug repositioning such as drug libraries and useful knowledge for bringing new drugs to market. Thus, a collaboration between researchers who establish efficient screening systems and pharmaceutical companies that own various drugs, including those that failed in clinical trials, can lead to a successful drug repositioning.

Although drug repositioning may be useful in the future, there are hurdles to the transition of this research into clinical practice owing to financial problems. Drug repositioning involves reinvestment in inexpensive drugs with expired patents; therefore, the benefits to pharmaceutical companies are small, which results in a reluctance to cooperate to broaden the indications of their drugs. This is especially true for rare diseases, such as glioma. Currently, the only way for researchers to raise public and private funds is by themselves, and they must conduct physician-led clinical trials without the support of pharmaceutical companies. An effective system in which the government supports drug repositioning is required to overcome the issue of budget constraints. From an economic perspective, it would be beneficial to patients and countries to treat patients with inexpensive drugs with expired patents.

After the appearance of TMZ, drug development for GBM has stagnated. A huge advance in the treatment of patients with GBM can be expected if effective drugs are identified via drug repurposing.


5. Conclusion

Drug repositioning is a useful research strategy to identify the therapeutic agents for glioma. Here, we discuss the current drug repositioning and its perspective for glioma treatment. Despite many efforts to date, no agents are widely used in the current clinical practice. For breaking down the current situation, appropriate screening system, suitable animal model, well-designed clinical trials, and tight collaboration with pharmaceutical companies are warranted. From now on, the drastic progress in this field would be occurred by new methods including AI.


Conflict of interest

All authors declare no conflict of interests for this article.



2-FPA2-fluoropalmitic acid
AIartificial intelligence
AMPKAMP-activated protein kinase
ASAacetylsalicylic acid
AT1Rangiotensin I receptors
AT2angiotensin II
BBBblood-brain barrier
CLIC1chloride intracellular channel 1
CNScentral nervous system
Cx43connexin 43
ERKextracellular signal-regulated kinase
FDAFood and Drug Administration
GDHglutamate dehydrogenase
GLI1glioma-associated oncogene homolog 1
GSCglioma stem-like cell
GSK3glycogen synthase kinase 3
HAThistone acetyltransferase
HDAChistone deacetylase
HDACihistone deacetylase inhibitor
IDHisocitrate dehydrogenase
MGMTO6-methylguanine-DNA methyltransferase
MMP-2matrix metalloproteinase-2
mTORmammalian target of rapamycin
NF-κBnuclear factor-kappaB
OSoverall survival
PFSprogression-free survival
PGE2prostaglandin E2
PRLphosphatase of regenerating liver
RdRPRNA-dependent RNA polymerase
ROCKRho-associated protein kinase
SHHsonic hedgehog
STAT3signal transducer and activator of transcription 3
TCFT-cell factor
TERTtelomerase reverse transcriptase
TGF-βtransforming growth factor-β
VEGFvascular endothelial growth factor
VPAvalproic acid
WHOWorld Health Organization


  1. 1. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro-Oncology. 2019;21(Suppl 5):v1-v100
  2. 2. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathologica. 2016;131(6):803-820
  3. 3. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro-Oncology. 2012;14(Suppl 5):v1-v49
  4. 4. Stupp R, Gander M, Leyvraz S, Newlands E. Current and future developments in the use of temozolomide for the treatment of brain tumours. The Lancet Oncology. 2001;2(9):552-560
  5. 5. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine. 2005;352(10):987-996
  6. 6. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England Journal of Medicine. 2005;352(10):997-1003
  7. 7. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochemical and Biophysical Research Communications. 2005;333(2):328-335
  8. 8. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. The New England Journal of Medicine. 2014;370(8):709-722
  9. 9. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. The New England Journal of Medicine. 2014;370(8):699-708
  10. 10. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. Journal of Clinical Oncology. 2009;27(20):3297-3302
  11. 11. Wurth R, Pattarozzi A, Gatti M, Bajetto A, Corsaro A, Parodi A, et al. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt. Cell Cycle. 2013;12(1):145-156
  12. 12. 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. Journal of BUON. 2014;19(2):502-511
  13. 13. Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, et al. Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Translational Medicine. 2012;1(11):811-824
  14. 14. Molenaar RJ, Coelen RJS, Khurshed M, Roos E, Caan MWA, van Linde ME, et al. Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours. BMJ Open. 2017;7(6):e014961
  15. 15. Zhang J, Li M, Song M, Chen W, Mao J, Song L, et al. Clic1 plays a role in mouse hepatocarcinoma via modulating Annexin A7 and Gelsolin in vitro and in vivo. Biomedicine & Pharmacotherapy. 2015;69:416-419
  16. 16. Tian Y, Guan Y, Jia Y, Meng Q, Yang J. Chloride intracellular channel 1 regulates prostate cancer cell proliferation and migration through the MAPK/ERK pathway. Cancer Biotherapy & Radiopharmaceuticals. 2014;29(8):339-344
  17. 17. Setti M, Savalli N, Osti D, Richichi C, Angelini M, Brescia P, et al. Functional role of CLIC1 ion channel in glioblastoma-derived stem/progenitor cells. Journal of the National Cancer Institute. 2013;105(21):1644-1655
  18. 18. Barbieri F, Verduci I, Carlini V, Zona G, Pagano A, Mazzanti M, et al. Repurposed Biguanide drugs in Glioblastoma exert Antiproliferative effects via the inhibition of intracellular Chloride Channel 1 activity. Frontiers in Oncology. 2019;9:135
  19. 19. Seliger C, Ricci C, Meier CR, Bodmer M, Jick SS, Bogdahn U, et al. Diabetes, use of antidiabetic drugs, and the risk of glioma. Neuro-Oncology. 2016;18(3):340-349
  20. 20. Seliger C, Genbrugge E, Gorlia T, Chinot O, Stupp R, Nabors B, et al. Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. International Journal of Cancer. 2020;146(3):803-809
  21. 21. Ager EI, Neo J, Christophi C. The renin-angiotensin system and malignancy. Carcinogenesis. 2008;29(9):1675-1684
  22. 22. Rivera E, Arrieta O, Guevara P, Duarte-Rojo A, Sotelo J. AT1 receptor is present in glioma cells; its blockage reduces the growth of rat glioma. British Journal of Cancer. 2001;85(9):1396-1399
  23. 23. Arrieta O, Guevara P, Escobar E, Garcia-Navarrete R, Pineda B, Sotelo J. Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. British Journal of Cancer. 2005;92(7):1247-1252
  24. 24. Januel E, Ursu R, Alkhafaji A, Marantidou A, Doridam J, Belin C, et al. Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma. European Journal of Neurology. 2015;22(9):1304-1309
  25. 25. Ursu R, Thomas L, Psimaras D, Chinot O, Le Rhun E, Ricard D, et al. Angiotensin II receptor blockers, steroids and radiotherapy in glioblastoma-a randomised multicentre trial (ASTER trial). An ANOCEF study. European Journal of Cancer. 2019;109:129-136
  26. 26. Tewarie IA, Senders JT, Hulsbergen AFC, Kremer S, Broekman MLD. Beta-blockers and glioma: A systematic review of preclinical studies and clinical results. Neurosurgical Review. 2020
  27. 27. Johansen MD, Urup T, Holst CB, Christensen IJ, Grunnet K, Lassen U, et al. Outcome of Bevacizumab therapy in patients with recurrent Glioblastoma treated with angiotensin system inhibitors. Cancer Investigation. 2018;36(9–10):512-519
  28. 28. Maklad A, Sharma A, Azimi I. Calcium signaling in brain cancers: Roles and therapeutic targeting. Cancers (Basel). 2019;11(2):145
  29. 29. Liu Z, Wei Y, Zhang L, Yee PP, Johnson M, Zhang X, et al. Induction of store-operated calcium entry (SOCE) suppresses glioblastoma growth by inhibiting the hippo pathway transcriptional coactivators YAP/TAZ. Oncogene. 2019;38(1):120-139
  30. 30. Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: What are the cancer relevant targets? Cancer Letters. 2009;277(1):8-21
  31. 31. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. The Journal of Biological Chemistry. 2001;276(39):36734-36741
  32. 32. Chinnaiyan P, Cerna D, Burgan WE, Beam K, Williams ES, Camphausen K, et al. Postradiation sensitization of the histone deacetylase inhibitor valproic acid. Clinical Cancer Research. 2008;14(17):5410-5415
  33. 33. Zhang C, Liu S, Yuan X, Hu Z, Li H, Wu M, et al. Valproic acid promotes human Glioma U87 cells apoptosis and inhibits glycogen synthase kinase-3beta through ERK/Akt signaling. Cellular Physiology and Biochemistry. 2016;39(6):2173-2185
  34. 34. Pyko IV, Nakada M, Sabit H, Teng L, Furuyama N, Hayashi Y, et al. Glycogen synthase kinase 3beta inhibition sensitizes human glioblastoma cells to temozolomide by affecting O6-methylguanine DNA methyltransferase promoter methylation via c-Myc signaling. Carcinogenesis. 2013;34(10):2206-2217
  35. 35. 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(12):1156-1164
  36. 36. Yuan Y, Xiang W, Qing M, Yanhui L, Jiewen L, Yunhe M. Survival analysis for valproic acid use in adult glioblastoma multiforme: A meta-analysis of individual patient data and a systematic review. Seizure. 2014;23(10):830-835
  37. 37. Barker CA, Bishop AJ, Chang M, Beal K, Chan TA. Valproic acid use during radiation therapy for glioblastoma associated with improved survival. International Journal of Radiation Oncology, Biology, Physics. 2013;86(3):504-509
  38. 38. Kerkhof M, Dielemans JC, van Breemen MS, Zwinkels H, Walchenbach R, Taphoorn MJ, et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro-Oncology. 2013;15(7):961-967
  39. 39. Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, et al. Does Valproic acid or Levetiracetam improve survival in Glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed Glioblastoma. Journal of Clinical Oncology. 2016;34(7):731-739
  40. 40. Bobustuc GC, Baker CH, Limaye A, Jenkins WD, Pearl G, Avgeropoulos NG, et al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro-Oncology. 2010;12(9):917-927
  41. 41. Scicchitano BM, Sorrentino S, Proietti G, Lama G, Dobrowolny G, Catizone A, et al. Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis. Cancer Cell International. 2018;18:136
  42. 42. Weyerhauser P, Kantelhardt SR, Kim EL. Re-purposing Chloroquine for Glioblastoma: Potential merits and confounding variables. Frontiers in Oncology. 2018;8:335
  43. 43. Verbaanderd C, Maes H, Schaaf MB, Sukhatme VP, Pantziarka P, Sukhatme V, et al. Repurposing drugs in oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience. 2017;11:781
  44. 44. Golden EB, Cho HY, Hofman FM, Louie SG, Schonthal AH, Chen TC. Quinoline-based antimalarial drugs: A novel class of autophagy inhibitors. Neurosurgical Focus. 2015;38(3):E12
  45. 45. Roy LO, Poirier MB, Fortin D. Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta. Investigational New Drugs. 2015;33(5):1020-1031
  46. 46. Sotelo J, Briceno E, Lopez-Gonzalez MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine. 2006;144(5):337-343
  47. 47. Pesanti EL, Cox C. Metabolic and synthetic activities of pneumocystis carinii in vitro. Infection and Immunity. 1981;34(3):908-914
  48. 48. Pathak MK, Dhawan D, Lindner DJ, Borden EC, Farver C, Yi T. Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Molecular Cancer Therapeutics. 2002;1(14):1255-1264
  49. 49. Bai Y, Yu ZH, Liu S, Zhang L, Zhang RY, Zeng LF, et al. Novel anticancer agents based on targeting the Trimer Interface of the PRL phosphatase. Cancer Research. 2016;76(16):4805-4815
  50. 50. Irons J. Fluvoxamine in the treatment of anxiety disorders. Neuropsychiatric Disease and Treatment. 2005;1(4):289-299
  51. 51. Hartter S, Wetzel H, Hammes E, Hiemke C. Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients. Psychopharmacology. 1993;110(3):302-308
  52. 52. Pollard TD, Borisy GG. Cellular motility driven by assembly and disassembly of actin filaments. Cell. 2003;112(4):453-465
  53. 53. Nurnberg A, Kitzing T, Grosse R. Nucleating actin for invasion. Nature Reviews. Cancer. 2011;11(3):177-187
  54. 54. Le Clainche C, Carlier MF. Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiological Reviews. 2008;88(2):489-513
  55. 55. Serrels B, Serrels A, Brunton VG, Holt M, McLean GW, Gray CH, et al. Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex. Nature Cell Biology. 2007;9(9):1046-1056
  56. 56. Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, et al. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nature Neuroscience. 2013;16(4):441-448
  57. 57. Hayashi K, Michiue H, Yamada H, Takata K, Nakayama H, Wei FY, et al. Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. Scientific Reports. 2016;6:23372
  58. 58. Wang SJ, Lu KT, Gean PW. Inhibition of synaptic transmission and epileptiform activity in central neurons by fluspirilene. British Journal of Pharmacology. 1997;120(6):1114-1118
  59. 59. Abhijnhan A, Adams CE, David A, Ozbilen M. Depot fluspirilene for schizophrenia. Cochrane Database of Systematic Reviews. 2007;1:CD001718
  60. 60. Galizzi JP, Fosset M, Romey G, Laduron P, Lazdunski M. Neuroleptics of the diphenylbutylpiperidine series are potent calcium channel inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 1986;83(19):7513-7517
  61. 61. Shi XN, Li H, Yao H, Liu X, Li L, Leung KS, et al. In Silico identification and In vitro and In vivo validation of anti-psychotic drug Fluspirilene as a potential CDK2 inhibitor and a candidate anti-cancer drug. PLoS One. 2015;10(7):e0132072
  62. 62. Dong Y, Furuta T, Sabit H, Kitabayashi T, Jiapaer S, Kobayashi M, et al. Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug. Oncotarget. 2017;8(67):111728-111741
  63. 63. Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Molecular Cancer Therapeutics. 2005;4(7):1086-1095
  64. 64. Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Molecular Cancer Therapeutics. 2008;7(7):2003-2011
  65. 65. Donoghue M, Lemery SJ, Yuan W, He K, Sridhara R, Shord S, et al. Eribulin mesylate for the treatment of patients with refractory metastatic breast cancer: Use of a “physician’s choice” control arm in a randomized approval trial. Clinical Cancer Research. 2012;18(6):1496-1505
  66. 66. Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, et al. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Research. 2004;64(16):5760-5766
  67. 67. Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, et al. Eribulin induces irreversible mitotic blockade: Implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Research. 2011;71(2):496-505
  68. 68. Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Science. 2014;105(10):1334-1342
  69. 69. Pawlik TM, Keyomarsi K. Role of cell cycle in mediating sensitivity to radiotherapy. International Journal of Radiation Oncology, Biology, Physics. 2004;59(4):928-942
  70. 70. Oehler C, von Bueren AO, Furmanova P, Broggini-Tenzer A, Orlowski K, Rutkowski S, et al. The microtubule stabilizer patupilone (epothilone B) is a potent radiosensitizer in medulloblastoma cells. Neuro-Oncology. 2011;13(9):1000-1010
  71. 71. Miki S, Imamichi S, Fujimori H, Tomiyama A, Fujimoto K, Satomi K, et al. Concomitant administration of radiation with eribulin improves the survival of mice harboring intracerebral glioblastoma. Cancer Science. 2018;109(7):2275-2285
  72. 72. Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathologica. 2013;126(2):267-276
  73. 73. Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife. 2015;4
  74. 74. Ozturk MB, Li Y, Tergaonkar V. Current insights to regulation and role of telomerase in human diseases. Antioxidants (Basel). 2017;6(1)
  75. 75. Maida Y, Yasukawa M, Furuuchi M, Lassmann T, Possemato R, Okamoto N, et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature. 2009;461(7261):230-235
  76. 76. Yamaguchi S, Maida Y, Yasukawa M, Kato T, Yoshida M, Masutomi K. Eribulin mesylate targets human telomerase reverse transcriptase in ovarian cancer cells. PLoS One. 2014;9(11):e112438
  77. 77. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature: New Biology. 1971;231(25):232-235
  78. 78. Qin LJ, Jia YS, Zhang YB, Wang YH. Cyclooxygenase inhibitor induces the upregulation of connexin-43 expression in C6 glioma cells. Biomed Reports. 2016;4(4):444-448
  79. 79. Lan F, Yue X, Han L, Yuan X, Shi Z, Huang K, et al. Antitumor effect of aspirin in glioblastoma cells by modulation of beta-catenin/T-cell factor-mediated transcriptional activity. Journal of Neurosurgery. 2011;115(4):780-788
  80. 80. Ming J, Sun B, Li Z, Lin L, Meng X, Han B, et al. Aspirin inhibits the SHH/GLI1 signaling pathway and sensitizes malignant glioma cells to temozolomide therapy. Aging (Albany NY). 2017;9(4):1233-1247
  81. 81. Seliger C, Schaertl J, Gerken M, Luber C, Proescholdt M, Riemenschneider MJ, et al. Use of statins or NSAIDs and survival of patients with high-grade glioma. PLoS One. 2018;13(12):e0207858
  82. 82. Farr M, Tunn EJ, Symmons DP, Scott DG, Bacon PA. Sulphasalazine in rheumatoid arthritis: Haematological problems and changes in haematological indices associated with therapy. British Journal of Rheumatology. 1989;28(2):134-138
  83. 83. Sleire L, Skeie BS, Netland IA, Forde HE, Dodoo E, Selheim F, et al. Drug repurposing: Sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system xc-, leading to glutathione depletion. Oncogene. 2015;34(49):5951-5959
  84. 84. Robe PA, Bentires-Alj M, Bonif M, Rogister B, Deprez M, Haddada H, et al. In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clinical Cancer Research. 2004;10(16):5595-5603
  85. 85. Robe PA, Martin DH, Nguyen-Khac MT, Artesi M, Deprez M, Albert A, et al. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer. 2009;9:372
  86. 86. Takeuchi S, Wada K, Nagatani K, Otani N, Osada H, Nawashiro H. Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma. Neurology India. 2014;62(1):42-47
  87. 87. Furuta T, Sabit H, Dong Y, Miyashita K, Kinoshita M, Uchiyama N, et al. Biological basis and clinical study of glycogen synthase kinase- 3beta-targeted therapy by drug repositioning for glioblastoma. Oncotarget. 2017;8:22811-22824
  88. 88. Kotliarova S, Pastorino S, Kovell LC, Kotliarov Y, Song H, Zhang W, et al. Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation. Cancer Research. 2008;68:6643-6651
  89. 89. Miyashita K, Kawakami K, Nakada M, Mai W, Shakoori A, Fujisawa H, et al. Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma. Clinical Cancer Research. 2009;15:887-897
  90. 90. Domoto T, Pyko IV, Furuta T, Miyashita K, Uehara M, Shimasaki T, et al. Glycogen synthase kinase-3beta is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Science. 2016;107:1363-1372
  91. 91. Kast RE, Karpel-Massler G, Halatsch ME. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget. 2014;5:8052-8082
  92. 92. Skaga E, Skaga IO, Grieg Z, Sandberg CJ, Langmoen IA, Vik-Mo EO. The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy. Journal of Cancer Research and Clinical Oncology. 2019;145:1495-1507
  93. 93. Gao L, Huang S, Zhang H, Hua W, Xin S, Cheng L, et al. Suppression of glioblastoma by a drug cocktail reprogramming tumor cells into neuronal like cells. Scientific Reports. 2019;9:3462
  94. 94. Zhang X, Liu X, Zhou W, Yang M, Ding Y, Wang Q, et al. Fasudil increases temozolomide sensitivity and suppresses temozolomide-resistant glioma growth via inhibiting ROCK2/ABCG2. Cell Death & Disease. 2018;9:190
  95. 95. Yuan J, Zhang F, Hallahan D, Zhang Z, He L, Wu LG, et al. Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors. Journal of Experimental & Clinical Cancer Research. 2018;37:181
  96. 96. Platten M, Wild-Bode C, Wick W, Leitlein J, Dichgans J, Weller M. N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor-beta release and reduces migration and invasiveness of human malignant glioma cells. International Journal of Cancer. 2001;93:53-61
  97. 97. Triscott J, Rose Pambid M, Dunn SE. Concise review: Bullseye: Targeting cancer stem cells to improve the treatment of gliomas by repurposing disulfiram. Stem Cells. 2015;33(4):1042-1046
  98. 98. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Reviews and Reports. 2011;7(2):292-306
  99. 99. Paranjpe A, Zhang R, Ali-Osman F, Bobustuc GC, Srivenugopal KS. Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis. 2014;35(3):692-702
  100. 100. Hothi P, Martins TJ, Chen L, Deleyrolle L, Yoon JG, Reynolds B, et al. High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells. Oncotarget. 2012;3(10):1124-1136
  101. 101. Huang J, Chaudhary R, Cohen AL, Fink K, Goldlust S, Boockvar J, et al. A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma. Journal of Neuro-Oncology. 2019;142(3):537-544
  102. 102. Koyuturk M, Ersoz M, Altiok N. Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-Jun N-terminal kinase. Neuroscience Letters. 2004;370(2–3):212-217
  103. 103. Afshordel S, Kern B, Clasohm J, Konig H, Priester M, Weissenberger J, et al. Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation—Impact of Ras-/rho-prenylation. Pharmacological Research. 2015;91:69-77
  104. 104. Gaist D, Hallas J, Friis S, Hansen S, Sorensen HT. Statin use and survival following glioblastoma multiforme. Cancer Epidemiology. 2014;38(6):722-727
  105. 105. Henker C, Kriesen T, Scherer M, Glass A, von Deimling A, Bendszus M, et al. Association between tumor compartment volumes, the incidence of pretreatment seizures, and statin-mediated protective effects in Glioblastoma. Neurosurgery. 2019;85(4):E722-E7e9
  106. 106. Xie Y, Lu Q, Lenahan C, Yang S, Zhou D, Qi X. Whether statin use improves the survival of patients with glioblastoma?: A meta-analysis. Medicine (Baltimore). 2020;99(9):e18997
  107. 107. Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM, et al. Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. European Journal of Biochemistry. 2000;267(19):5983-5994
  108. 108. Doble BW, Woodgett JR. GSK-3: Tricks of the trade for a multi-tasking kinase. Journal of Cell Science. 2003;116(Pt 7):1175-1186
  109. 109. Cohen P, Goedert M. GSK3 inhibitors: Development and therapeutic potential. Nature Reviews. Drug Discovery. 2004;3(6):479-487
  110. 110. Kitabayashi T, Dong Y, Furuta T, Sabit H, Jiapaer S, Zhang J, et al. Identification of GSK3beta inhibitor kenpaullone as a temozolomide enhancer against glioblastoma. Scientific Reports. 2019;9(1):10049
  111. 111. Tran NL, McDonough WS, Savitch BA, Fortin SP, Winkles JA, Symons M, et al. Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome. Cancer Research. 2006;66(19):9535-9542
  112. 112. Jiapaer S, Furuta T, Dong Y, Kitabayashi T, Sabit H, Zhang J, et al. Identification of 2-fluoropalmitic acid as a potential therapeutic agent against glioblastoma. Current Pharmaceutical Design. DOI: 10.2174/1381612826666200429092742
  113. 113. Wu H, Li X, Feng M, Yao L, Deng Z, Zao G, et al. Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway. Oncology Reports. 2018;40(6):3285-3296
  114. 114. Aroui S, Aouey B, Chtourou Y, Meunier AC, Fetoui H, Kenani A. Naringin suppresses cell metastasis and the expression of matrix metalloproteinases (MMP-2 and MMP-9) via the inhibition of ERK-P38-JNK signaling pathway in human glioblastoma. Chemico-Biological Interactions. 2016;244:195-203
  115. 115. Chen X, Zhang M, Gan H, Wang H, Lee JH, Fang D, et al. A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma. Nature Communications. 2018;9(1):2949
  116. 116. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiology of Disease. 2010;37(1):13-25
  117. 117. Pardridge WM. The blood-brain barrier: Bottleneck in brain drug development. NeuroRx. 2005;2(1):3-14
  118. 118. Ha SW, Hwang K, Jin J, Cho AS, Kim TY, Hwang SI, et al. Ultrasound-sensitizing nanoparticle complex for overcoming the blood-brain barrier: An effective drug delivery system. International Journal of Nanomedicine. 2019;14:3743-3752
  119. 119. Sugiyama S, Yamashita Y, Kikuchi T, Sonoda Y, Kumabe T, Tominaga T. Enhanced antitumor effect of combined-modality treatment using convection-enhanced delivery of hydrophilic nitrosourea with irradiation or systemic administration of temozolomide in intracranial brain tumor xenografts. Neurological Research. 2008;30(9):960-967
  120. 120. Tosi U, Souweidane MM. Longitudinal monitoring of Gd-DTPA following convection enhanced delivery in the brainstem. World Neurosurgery. 2020;137:38-42
  121. 121. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396-1401
  122. 122. Hoshino T, Wilson CB, Rosenblum ML, Barker M. Chemotherapeutic implications of growth fraction and cell cycle time in glioblastomas. Journal of Neurosurgery. 1975;43(2):127-135
  123. 123. Chou FH, Tsai KY, Su CY, Lee CC. The incidence and relative risk factors for developing cancer among patients with schizophrenia: A nine-year follow-up study. Schizophrenia Research. 2011;129(2–3):97-103

Written By

Sho Tamai, Nozomi Hirai, Shabierjiang Jiapaer, Takuya Furuta and Mitsutoshi Nakada

Submitted: March 5th, 2020 Reviewed: May 12th, 2020 Published: July 14th, 2020