Mechanistic investigation of synergistic interaction of tocopherol succinate with a quinoline-based inhibitor of mammalian target of rapamycin.

Autor:	Behera C; Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.; Department of Biotechnology, Guru Nanak Dev University, Amritsar, India., Kour J; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India., Banjare N; Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India., Verma PK; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India., Chashoo G; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India., Sawant SD; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Gupta PN; Formulation and Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 2022 Apr 20; Vol. 74 (4), pp. 605-617.
DOI:	10.1093/jpp/rgab122
Abstrakt:	Objectives: Cancer monotherapy is associated with various limitations; therefore, combination chemotherapy is widely explored for optimum drug efficacy. In this study, 4-(N-Phenyl-N'-substituted benzenesulfonyl)-6-(4-hydroxyphenyl) quinoline-based mammalian target of rapamycin (mTOR) inhibitor (IIIM-4Q) was investigated in combination with tocopherol succinate (TOS), and the mechanism of cytotoxicity was elucidated. Methods: The cytotoxic potential of IIIM-4Q and TOS was evaluated in five cell lines. Further, to understand the mechanism of cytotoxicity of IIIM-4Q, TOS and their combination, various studies including morphological analysis using scanning electron microscopy and 6-diamidino-2-phenylindole (DAPI) staining, estimation of reactive oxygen species (ROS) level, measurement of mitochondrial membrane potential (MMP), in-vitro cell migration assay, Western blotting and staining with acridine orange (AO) for autophagy detection were performed. Key Findings: Investigated combination was synergistic in nature and exhibited greater oxidative stress and mitochondrial dysfunction in pancreatic cancer cells. The migration potential of MIA PaCa-2 cells was significantly mitigated under the influence of this combination, and morphological changes such as chromatin condensation and nuclear blebbing were observed. Also, poly (adenosine diphosphate-ribose) polymerase cleavage and caspase-3 activation were observed in IIIM-4Q and TOS combination-treated cells. Conclusions: The investigated combination synergistically inhibited proliferation of MIA PaCa-2 cells through simultaneous induction of autophagy followed by apoptosis, and this combination demonstrated potential for further translational studies. (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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