The list of candidate agents.
Abstract
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.
Keywords
- 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 agent | Original indication disease | Mechanism of original disease | Mechanism of anti-glioma effect | CT | Refs. | |
---|---|---|---|---|---|---|
2.1 Antidiabetic drugs | 2.1.1 Metformin | Diabetes mellitus | Suppress gluconeogenesis in the liver | Activate AMPK Inhibit glutamate dehydrogenase |
NY | [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20] |
2.2 Antihypertensive drugs | 2.2.1 Angiotensin II receptor blocker | Hypertension | Block angiotensin II receptor | Inhibit vascular endothelial growth factor | III | [21, 22, 23, 24, 25] |
2.2.2 β-blocker | Hypertension | Block β receptor | Decrease cAMP levels | NY | [26, 27] | |
2.2.3 Calcium channel blocker | Hypertension | Block calcium channel | Inhibit hippo pathway | NY | [28, 29] | |
2.3 Antiepileptic drugs | 2.3.1 Valproic acid | Epilepsy | Block sodium channel | Inhibit GSK3β | NY | [31, 32, 33, 34, 35, 36, 37, 38, 39] |
2.3.2 Levetiracetam | Epilepsy | Block calcium channel | Inhibit MGMT expression | II | [40, 41] | |
2.4 Pesticides | 2.4.1 Chloroquine | Malaria ( |
Inhibit heme polymerization | Inhibit TGF-β and NF-κB | II | [42, 43, 44, 45, 46] |
2.4.2 Pentamidine | Pneumocystis pneumonia | Inhibition of glucose metabolism, protein synthesis, amino acid transport and ribonucleic acid synthesis | Unknown | NY | [47, 48, 49] | |
2.5 Antipsychotic drugs | 2.5.1 Fluvoxamine | Depression | Selective serotonin reuptake inhibitor | Suppress the activity of actin polymerization regulators | NY | [50, 51, 52, 53, 54, 55, 56, 57] |
2.5.2 Fluspirilene | Schizophrenia | Dephenylbutylpiperidine | Inhibit activation of STAT3 | NY | [58, 59, 60, 61, 62] | |
2.6 Antineoplastic drugs | 2.6.1 Eribulin | Breast cancer | Inhibit of microtubule activity | Inhibitor of telomerase reverse transcriptase- RNA-dependent | II | [63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76] |
2.7 Anti-inflammatory drugs | 2.7.1 Acetylsalicylic acid drugs | Fever, inflammation disease | Inhibit cyclooxygenase | Activate connexin 43, suppress Wnt/β-catenin/T-cell factor signaling and SHH/GLI1 pathway | NY | [77, 78, 79, 80, 81] |
2.7.2 Sulfasalazine | Rheumatoid arthritis | Block activation of NF-κB | Block activation of NF-κB | I/II | [82, 83, 84, 85, 86] | |
2.8 Multiple drug combination therapy | 2.8.1 CLOVA cocktail | – | – | Inhibit GSK3β | I/II | [87, 88, 89, 90] |
2.8.2 CUSP9* treatment | – | – | Suppress multiple molecule pathway | NY | [91, 92] | |
2.8.3 FTT cocktail | – | – | Inhibit ROCK2/moesin/β-catenin pathway, suppress TGF-β | NY | [93, 94, 95, 96] | |
2.9 Other drugs | 2.9.1 Disulfiram | Alcoholism | Inhibitor of ALDH | Inhibiting polo-like kinese-1 | II | [97, 98, 99, 100, 101] |
2.9.2 Statins | Dyslipidemia | Inhibited 3-hydroxy-3-methylglutaryl-coenzyme A reductase | Activate transcription factor-2 and c-jun, suppress ERK | NY | [102, 103, 104, 105, 106] | |
2.10 Pre drugs | 2.10.1 Kenpaullone | - | - | Inhibit GSK3β | NY | [107, 108, 109, 110, 111] |
2.10.2 2-Fluoropalmitic acid | - | - | Dephosphorylate ERK, suppress MMP-2 | NY | [112, 113, 114, 115] |
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].
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].
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
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).
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,
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).
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.
Abbreviations
2-FPA | 2-fluoropalmitic acid |
AI | artificial intelligence |
AMPK | AMP-activated protein kinase |
ASA | acetylsalicylic acid |
AT1R | angiotensin I receptors |
AT2 | angiotensin II |
BBB | blood-brain barrier |
BEV | bevacizumab |
CHQ | chloroquine |
CLIC1 | chloride intracellular channel 1 |
CNS | central nervous system |
Cx43 | connexin 43 |
D-2HG | D-2-hydroxyglutarate |
DSF | disulfiram |
ERK | extracellular signal-regulated kinase |
FDA | Food and Drug Administration |
GBM | glioblastoma |
GDH | glutamate dehydrogenase |
GLI1 | glioma-associated oncogene homolog 1 |
GSC | glioma stem-like cell |
GSK3 | glycogen synthase kinase 3 |
HAT | histone acetyltransferase |
HDAC | histone deacetylase |
HDACi | histone deacetylase inhibitor |
IDH | isocitrate dehydrogenase |
LEV | levetiracetam |
MGMT | O6-methylguanine-DNA methyltransferase |
MMP-2 | matrix metalloproteinase-2 |
mTOR | mammalian target of rapamycin |
NF-κB | nuclear factor-kappaB |
OS | overall survival |
PFS | progression-free survival |
PGE2 | prostaglandin E2 |
PRL | phosphatase of regenerating liver |
RdRP | RNA-dependent RNA polymerase |
ROCK | Rho-associated protein kinase |
SAS | sulfasalazine |
SHH | sonic hedgehog |
STAT3 | signal transducer and activator of transcription 3 |
TCF | T-cell factor |
TERT | telomerase reverse transcriptase |
TGF-β | transforming growth factor-β |
TMZ | temozolomide |
VEGF | vascular endothelial growth factor |
VPA | valproic acid |
WHO | World Health Organization |
References
- 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ager EI, Neo J, Christophi C. The renin-angiotensin system and malignancy. Carcinogenesis. 2008; 29 (9):1675-1684 - 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.
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.
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.
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.
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.
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.
Maklad A, Sharma A, Azimi I. Calcium signaling in brain cancers: Roles and therapeutic targeting. Cancers (Basel). 2019; 11 (2):145 - 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.
Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: What are the cancer relevant targets? Cancer Letters. 2009; 277 (1):8-21 - 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Weyerhauser P, Kantelhardt SR, Kim EL. Re-purposing Chloroquine for Glioblastoma: Potential merits and confounding variables. Frontiers in Oncology. 2018; 8 :335 - 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.
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.
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.
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.
Pesanti EL, Cox C. Metabolic and synthetic activities of pneumocystis carinii in vitro. Infection and Immunity. 1981; 34 (3):908-914 - 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.
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.
Irons J. Fluvoxamine in the treatment of anxiety disorders. Neuropsychiatric Disease and Treatment. 2005; 1 (4):289-299 - 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.
Pollard TD, Borisy GG. Cellular motility driven by assembly and disassembly of actin filaments. Cell. 2003; 112 (4):453-465 - 53.
Nurnberg A, Kitzing T, Grosse R. Nucleating actin for invasion. Nature Reviews. Cancer. 2011; 11 (3):177-187 - 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.
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.
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.
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.
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.
Abhijnhan A, Adams CE, David A, Ozbilen M. Depot fluspirilene for schizophrenia. Cochrane Database of Systematic Reviews. 2007; 1 :CD001718 - 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife. 2015; 4 - 74.
Ozturk MB, Li Y, Tergaonkar V. Current insights to regulation and role of telomerase in human diseases. Antioxidants (Basel). 2017; 6 (1) - 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.
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.
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature: New Biology. 1971; 231 (25):232-235 - 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cohen P, Goedert M. GSK3 inhibitors: Development and therapeutic potential. Nature Reviews. Drug Discovery. 2004; 3 (6):479-487 - 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.
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.
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.
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.
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.
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.
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.
Pardridge WM. The blood-brain barrier: Bottleneck in brain drug development. NeuroRx. 2005; 2 (1):3-14 - 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.
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.
Tosi U, Souweidane MM. Longitudinal monitoring of Gd-DTPA following convection enhanced delivery in the brainstem. World Neurosurgery. 2020; 137 :38-42 - 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.
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.
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