*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.

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

**Figure 2.**

GBM, did not show any difference in steroid requirements or a significant increase

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

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

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.

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

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 clini-

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

cal benefit of VPA combination treatment in patients with GBM was

contraindicated [35–39], and further studies are warranted.

ongoing and the results are expected in the future.

in the median OS [25].

*2.2.3 Calcium channel blocker*

**2.3 Antiepileptic drugs**

migration and angiogenesis [30].

*2.3.1 Valproic acid*

*2.3.2 Levetiracetam*

**140**

*2.2.2 β-Blocker*

PFS [27].

*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.*

#### **2.4 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 (doubleblind, 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.

survival in an intracranial xenograft mouse model [62]. These results suggest that

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

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 eribulininduced 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

*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.*

fluspirilene is a potential novel anti-glioma candidate.

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

**2.6 Antineoplastic drugs**

recurrent GBM (UMIN ID: 000030359).

**Figure 3.**

**143**

*2.6.1 Eribulin*

#### **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 [52–54]. 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.
