1. Novel isoniazid-hydrazone derivatives induce cell growth inhibition, cell cycle arrest and apoptosis via mitochondria-dependent caspase activation and PI3K/AKT inhibition.
- Author
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Rouzi K, Altay A, Bouatia M, Yeniçeri E, Islam MS, Oulmidi A, El Karbane M, and Karrouchi K
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Phosphoinositide-3 Kinase Inhibitors pharmacology, Phosphoinositide-3 Kinase Inhibitors chemistry, Phosphoinositide-3 Kinase Inhibitors chemical synthesis, Mice, Animals, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Apoptosis drug effects, Phosphatidylinositol 3-Kinases metabolism, Cell Proliferation drug effects, Hydrazones pharmacology, Hydrazones chemistry, Hydrazones chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Cycle Checkpoints drug effects, Mitochondria drug effects, Mitochondria metabolism, Drug Screening Assays, Antitumor, Dose-Response Relationship, Drug, Caspases metabolism, Isoniazid pharmacology, Isoniazid chemistry
- Abstract
In this study, seven isoniazid-hydrazone derivatives (3a-g) were synthesized and their structures elucidated by chromatographic techniques, and then the antiproliferative effects of these compounds on various cancer cells were tested. The advanced anticancer mechanism of the most potent compound was then investigated. Antiproliferative activities of the synthesized compounds were evaluated on human breast cancer MCF-7, lung cancer A-549, colon cancer HT-29, and non-cancerous mouse fibroblast 3T3-L1 cell lines by XTT assay. Flow cytometry analysis were carried out to determine cell cycle distribution, apoptosis, mitochondrial membrane potential, multi-caspase activity, and expression of PI3K/AKT signaling pathway. The XTT results showed that all the title molecules displayed cytotoxic activity at varying strengths in different dose ranges, and among them, the strongest cytotoxic effect and high selectivity were exerted by 3d against MCF-7 cells with the IC
50 value of 11.35 µM and selectivity index of 8.65. Flow cytometry results revealed that compound 3d induced apoptosis through mitochondrial membrane disruption and multi-caspase activation in MCF-7 cells. It also inhibited the cell proliferation via inhibition of expression of PI3K/AKT and arrested the cell cycle at G0/G1 phase. In conclusion, all these data disclosed that among the synthesized compounds, 3d is notable for in vivo anticancer studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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