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Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity

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Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, P.O. Box 553, 33101 Tampere, Finland
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BioMediTech Institute and Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, 33520 Tampere, Finland
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Science Center, Tampere University Hospital, Arvo Ylpön katu 34, 33520 Tampere, Finland
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Department of Biotechnology, Lady Doak College, Thallakulam, Madurai 625002, India
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Faculty of Engineering and Natural Sciences, Tampere University, P.O. Box 553, 33101 Tampere, Finland
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Computational Systems Biology Group, Faculty of Medicine and Health Technology, Tampere University, P.O. Box 553, 33101 Tampere, Finland
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Institute for Systems Biology, 1441N 34th Street, Seattle, WA 98103, USA
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Author to whom correspondence should be addressed.
Academic Editor: Markus Siegelin
Cells 2021, 10(8), 1975; https://doi.org/10.3390/cells10081975
Received: 3 July 2021 / Revised: 28 July 2021 / Accepted: 28 July 2021 / Published: 3 August 2021
(This article belongs to the Section Cell Signaling)
Drug resistance and tumor heterogeneity limits the therapeutic efficacy in treating glioblastoma, an aggressive infiltrative type of brain tumor. GBM cells develops resistance against chemotherapeutic agent, temozolomide (TMZ), which leads to the failure in treatment strategies. This enduring challenge of GBM drug resistance could be rational by combinatorial targeted therapy. Here, we evaluated the combinatorial effect of phenolic compound (2-(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), GPR17 agonist 2-({5-[3-(Morpholine-4-sulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)-N-[4-(propan-2-yl)phenyl]acetamide (T0510.3657 or T0) with the frontline drug, TMZ, on the inhibition of GBM cells. Mesenchymal cell lines derived from patients’ tumors, MMK1 and JK2 were treated with the combination of THTMP + T0, THTMP + TMZ and T0 + TMZ. Cellular migration, invasion and clonogenicity assays were performed to check the migratory behavior and the ability to form colony of GBM cells. Mitochondrial membrane permeability (MMP) assay and intracellular calcium, [Ca2+]i, assay was done to comprehend the mechanism of apoptosis. Role of apoptosis-related signaling molecules was analyzed in the induction of programmed cell death. In vivo validation in the xenograft models further validates the preclinical efficacy of the combinatorial drug. GBM cells exert better synergistic effect when exposed to the cytotoxic concentration of THTMP + T0, than other combinations. It also inhibited tumor cell proliferation, migration, invasion, colony-forming ability and cell cycle progression in S phase, better than the other combinations. Moreover, the combination of THTMP + T0 profoundly increased the [Ca2+]i, reactive oxygen species in a time-dependent manner, thus affecting MMP and leading to apoptosis. The activation of intrinsic apoptotic pathway was regulated by the expression of Bcl-2, cleaved caspases-3, cytochrome c, HSP27, cIAP-1, cIAP-2, p53, and XIAP. The combinatorial drug showed promising anti-tumor efficacy in GBM xenograft model by reducing the tumor volume, suggesting it as an alternative drug to TMZ. Our findings indicate the coordinated administration of THTMP + T0 as an efficient therapy for inhibiting GBM cell proliferation. View Full-Text
Keywords: glioblastoma; mesenchymal GBM; alkylaminophenol; GPR17 agonist; synergy; cell cycle arrest; intrinsic apoptotic pathway glioblastoma; mesenchymal GBM; alkylaminophenol; GPR17 agonist; synergy; cell cycle arrest; intrinsic apoptotic pathway
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MDPI and ACS Style

Doan, P.; Nguyen, P.; Murugesan, A.; Candeias, N.R.; Yli-Harja, O.; Kandhavelu, M. Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity. Cells 2021, 10, 1975. https://doi.org/10.3390/cells10081975

AMA Style

Doan P, Nguyen P, Murugesan A, Candeias NR, Yli-Harja O, Kandhavelu M. Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity. Cells. 2021; 10(8):1975. https://doi.org/10.3390/cells10081975

Chicago/Turabian Style

Doan, Phuong, Phung Nguyen, Akshaya Murugesan, Nuno R. Candeias, Olli Yli-Harja, and Meenakshisundaram Kandhavelu. 2021. "Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity" Cells 10, no. 8: 1975. https://doi.org/10.3390/cells10081975

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