**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 O<sup>6</sup> 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**).

#### **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 [15–17]. 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].

**Candidate agent**

2.1 Antidiabetic drugs 2.1.1 Metformin

**137**

2.2 drugs

Antihypertensive

2.2.1 Angiotensin II

Hypertension

Block angiotensin II receptor

> receptor blocker

2.2.2 β-blocker

2.2.3 Calcium channel blocker

> 2.3 Antiepileptic

> 2.3.1 Valproic acid Epilepsy

2.3.2 Levetiracetam

> 2.4 Pesticides

2.5 Antipsychotic

2.5.1 Fluvoxamine

2.5.2 Fluspirilene

> 2.6

drugs

2.7 drugs

Anti-inflammatory

2.7.1 Acetylsalicylic

Fever, inflammation

 disease

 Inhibit

cyclooxygenase

> acid drugs

2.7.2 Sulfasalazine

2.8.1 CLOVA

cocktail

2.8.2 CUSP9\*

–

 –

 –

treatment

2.8.3 FTT cocktail –

2.8 Multiple drug combination therapy

 Rheumatoid arthritis

–

 Block activation of NF-κB

 –

Antineoplastic

2.6.1 Eribulin

 Schizophrenia

 Breast cancer

Dephenylbutylpiperidine

Inhibit of microtubule activity

 Depression

drugs

 2.4.1 Chloroquine 2.4.2 Pentamidine

 Malaria (*Plasmodium* spp.)

 Pneumocystis

 pneumonia

 Inhibition of glucose metabolism, protein synthesis, amino

acid transport and ribonucleic acid synthesis

Selective serotonin reuptake inhibitor

 Inhibit heme

polymerization

 Epilepsy

Block calcium channel

drugs

 Hypertension Hypertension

Block β receptor Block calcium channel Block sodium channel

 **Original indication disease**

 Diabetes mellitus

 **Mechanism of original disease**

Suppress

gluconeogenesis

 in the liver

**Mechanism of anti-glioma effect**

Activate AMPK Inhibit glutamate Inhibit vascular endothelial growth factor

Decrease cAMP levels Inhibit hippo pathway

Inhibit GSK3β Inhibit MGMT expression

Inhibit TGF-β and NF-κB

Unknown Suppress the activity of actin

regulators

Inhibit activation of STAT3 Inhibitor of telomerase reverse transcriptase-

dependent Activate connexin 43, suppress factor signaling and SHH/GLI1 pathway

Block activation of NF-κB

Inhibit GSK3β Suppress multiple molecule pathway

Inhibit

TGF-β

ROCK2/moesin/β-catenin

 pathway, suppress

NY [93–96]

Wnt/β-catenin/T-cell

NY [77–81] I/II [82–86] I/II [87–90] NY [91, 92]

polymerization

NY [50–57] NY [58–62]

> RNA-

II [63–76]

dehydrogenase

**CT Refs.**

NY [10–20]

III [21–25] NY [26, 27] NY [28, 29]

*DOI: http://dx.doi.org/10.5772/intechopen.92803*

NY [31–39]

II [40, 41] II [42–46] NY [47–49]

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

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


#### *Drug Repositioning for the Treatment of Glioma: Current State and Future Perspective DOI: http://dx.doi.org/10.5772/intechopen.92803*

Approximately half of the cases of GBM have a methylation of the

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

radiotherapy [6]. MGMT potentially removes methyl adducts at the O


of guanine and indicates resistance to alkylating agents; however, the methylation of the MGMT promoter interferes with MGMT activity and induces glioma

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

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

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

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)

G1/S transition, and metformin causes G1 cell cycle arrest in GSCs by the selective

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

–17]. CLIC1 is involved in the regulation of the

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

the issues of drug repositioning in malignant glioma.

**2. Current candidate agents for glioma**

<sup>6</sup> position

O6

cell death [6].

are still unknown.

**2.1 Antidiabetic drugs**

various cancers, including GBM [15

inhibition of CLIC1 [18].

**136**

*2.1.1 Metformin*


**Table 1.**

*transcription 3; TGF-β, tumor growth factor-β.* pooled analysis that included 1731 patients from large-scale randomized controlled trials, the use of metformin was not significantly associated with OS or progressionfree 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

*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*

*αKG reduction in*

*FOXO3 via activating AMPK. The inhibition of GDH reduces the D-2HG production via*

*IDH 1/2 mutation glioma. Selective inhibition of CLIC1 causes G1 cell cycle arrest in GSCs.*

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

*DOI: http://dx.doi.org/10.5772/intechopen.92803*

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 angiotensinconverting 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, placebocontrolled trial, which included losartan to the current treatment for patients with

results in the future.

**Figure 1.**

**139**

**2.2 Antihypertensive drugs**

*2.2.1 Angiotensin II (AT2) receptor blocker*

*The list of candidate agents.* *Drug Repositioning for the Treatment of Glioma: Current State and Future Perspective DOI: http://dx.doi.org/10.5772/intechopen.92803*

#### **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.*

pooled analysis that included 1731 patients from large-scale randomized controlled trials, the use of metformin was not significantly associated with OS or progressionfree 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 angiotensinconverting 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, placebocontrolled trial, which included losartan to the current treatment for patients with

**Candidate agent**

> 2.9 Other drugs

**138**

 2.9.1 Disulfiram

2.9.2 Statins

> 2.10 Pre drugs

> 2.10.1 Kenpaullone

2.10.2 2-


Fluoropalmitic

 *AMPK,*  *methyltransferase;*

 *MMP-2, matrix* 

*AMP-activated*

 *protein kinase; CT, clinical trial; ERK, extracellular* 

*metalloproteinase-2;*

 *NF-κB, nuclear factor- kappaB; NY, not yet; ROCK2, Rho-associated*

*signal-regulated*

 *kinase; GLI1,* 

*glioma-associated*

 *protein kinase 2; SHH, sonic hedgehog; STAT3, signal transducer and activator of*

 *oncogene homolog 1; GSK3β, glycogen synthase kinase 3β; MGMT,*

*ALDH, aldehyde dehydrogenase;*

*O6-methylguanine-DNA*

*transcription 3; TGF-β, tumor growth factor-β.*

**Table 1.** *The list of candidate agents.*

 acid

 -

 Alcoholism

 Dyslipidemia

 **Original indication disease**

 **Mechanism of original disease**

Inhibitor of ALDH

Inhibited reductase



3-hydroxy-3-methylglutaryl-coenzyme

 A

Activate transcription

ERK

Inhibit GSK3β Dephosphorylate

 ERK, suppress MMP-2

 factor-2 and c-jun, suppress

**Mechanism of anti-glioma effect**

Inhibiting polo-like kinese-1

**CT Refs.** II [97–101]

NY [102–106]

NY [107–111] NY [112–115]

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

GBM, did not show any difference in steroid requirements or a significant increase in the median OS [25].
