*2.7.1 Acetylsalicylic acid (ASA)*

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

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

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

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

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

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

The CLOVA cocktail, composed of cimetidine, lithium, olanzapine, and valproate, targets dysregulated GSK3β in GBM [87–89]. 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

would be limited.

*2.8.1 CLOVA cocktail*

*2.8.2 CUSP9\* treatment*

*2.8.3 FTT cocktail*

**145**

**2.8 Multiple-drug combination therapy**

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

control group treated with TMZ alone [87].

via the blockade of the Wnt/β-catenin pathway [92].

recurrent GBM with multiple existing drugs (**Figure 5**).
