Novel Treatment Strategies for Glioblastoma: Therapeutic Potential of Phenolic Derivatives and Orphan G-protein Coupled Receptor Ligand

Glioblastoma (GBM) is a prevalent brain tumor with a high mortality rate worldwide. Although many efforts have been made to explore potential therapeutic strategies, the treatment for GBM remains obscure. Phenolic compounds have received considerable attention in cancer biology owing to their therapeutic applications. Indeed, phenolic compounds with alkylaminophenol core have been approved by the U.S. Food and Drug Administration to treat several diseases. The present study aims at exploring the anti-tumor activity of three different alkylaminophenols, namely 2-((3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), 2- ((1,2,3,4-tetrahydroquinolin-1-yl)(4-methoxyphenyl)methyl)phenol (THMPP), and N-(2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl)indoline (HNPMI) against GBM cell growth and proliferation. Our results reveal that THTMP has potent inhibitory activity against GBM cells and could target GBM cancer stem cells (GSCs) via arresting the cell cycle at the G1/S phase and inducing reactive oxygen species- mediated apoptosis. Furthermore, THTMP could target GSCs by modulating epidermal growth factor receptor (EGFR) and GSC signaling pathways. In addition, the G-protein coupled receptor 17 (GPR17) targeted signaling pathway has also grasped attention in the treatment of GBM. Our preliminary study has revealed that GPR17 interaction with its ligand, 2-[[5-(3-morpholin-4-ylsulfonylphenyl)-4-[4- (trifluoromethoxy) phenyl]-1,2,4-triazol-3-yl] sulfanyl]-N-(4-propan-2ylphenyl) acetamide (namely, T0510.3657 or T0), could potentially regulate the intracellular signaling communication of GBM. We have identified that T0 downregulates the concentration of adenosine 3',5'-cyclic monophosphate (cAMP) through activating GPR17 signaling. Here, we have characterized the effect of T0 and the underlying molecular mechanism in inducing GBM cell death.

Towards combinatorial drug development, the lead phenolic compound and the GPR17 ligand were used to investigate the anti-cancer effect against GBM. The results show that THTMP has a higher synergistic effect when combined with T0 than the temozolomide (TMZ) in inducing GBM cell death. Furthermore, this study reveals that combining THTMP with T0 would increase the inhibitory effect against mesenchymal GBM cells compared to a single THTMP/T0/TMZ treatment. In addition, the combination THTMP+T0 could decrease the migration, invasion, and colony formation ability of glioblastoma cells. The combination also has the ability to arrest the cell cycle at the S phase as well as to induce ROS-, caspase- and mitogen-activated protein kinase (MAPK)-mediated apoptosis. The activation of intrinsic apoptosis is found to be regulated by XIAP, p53, cIAP-1, cIAP-2, HSP27, cytochrome c, cleaved caspases-3, and Bcl-2. The combinatorial drug treatment shows the promising anti-tumor property in the GBM xenograft model since it can reduce tumor volume. Our findings imply the coordinated administration of THTMP and T0 as a potential therapy that can be used for GBM treatment.