Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity
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 challe...
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MDPI AG
2021-08-01
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| author | Phuong Doan Phung Nguyen Akshaya Murugesan Nuno R. Candeias Olli Yli-Harja Meenakshisundaram Kandhavelu |
| author_facet | Phuong Doan Phung Nguyen Akshaya Murugesan Nuno R. Candeias Olli Yli-Harja Meenakshisundaram Kandhavelu |
| author_sort | Phuong Doan |
| collection | DOAJ |
| description | 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)(<i>p</i>-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, [Ca<sup>2+</sup>]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 [Ca<sup>2+</sup>]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. |
| first_indexed | 2024-03-10T08:55:24Z |
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| language | English |
| last_indexed | 2024-03-10T08:55:24Z |
| publishDate | 2021-08-01 |
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| spelling | doaj.art-40d414a1769a46f49228fbed163349db2023-11-22T07:09:59ZengMDPI AGCells2073-44092021-08-01108197510.3390/cells10081975Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death ActivityPhuong Doan0Phung Nguyen1Akshaya Murugesan2Nuno R. Candeias3Olli Yli-Harja4Meenakshisundaram Kandhavelu5Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, P.O. Box 553, 33101 Tampere, FinlandMolecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, P.O. Box 553, 33101 Tampere, FinlandMolecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, P.O. Box 553, 33101 Tampere, FinlandFaculty of Engineering and Natural Sciences, Tampere University, P.O. Box 553, 33101 Tampere, FinlandBioMediTech Institute and Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, 33520 Tampere, FinlandMolecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, P.O. Box 553, 33101 Tampere, FinlandDrug 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)(<i>p</i>-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, [Ca<sup>2+</sup>]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 [Ca<sup>2+</sup>]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.https://www.mdpi.com/2073-4409/10/8/1975glioblastomamesenchymal GBMalkylaminophenolGPR17 agonistsynergycell cycle arrest |
| spellingShingle | Phuong Doan Phung Nguyen Akshaya Murugesan Nuno R. Candeias Olli Yli-Harja Meenakshisundaram Kandhavelu Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity Cells glioblastoma mesenchymal GBM alkylaminophenol GPR17 agonist synergy cell cycle arrest |
| title | Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity |
| title_full | Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity |
| title_fullStr | Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity |
| title_full_unstemmed | Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity |
| title_short | Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity |
| title_sort | alkylaminophenol and gpr17 agonist for glioblastoma therapy a combinational approach for enhanced cell death activity |
| topic | glioblastoma mesenchymal GBM alkylaminophenol GPR17 agonist synergy cell cycle arrest |
| url | https://www.mdpi.com/2073-4409/10/8/1975 |
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