期刊
MOLECULES
卷 27, 期 22, 页码 -出版社
MDPI
DOI: 10.3390/molecules27227993
关键词
ciprofloxacin derivative; HepG2; A549 cancer cells; apoptosis; necro-apoptosis; RIPK1; RIPK3; MLKL pathway; LDH; caspase 3
资金
- JSPS KAKENHI [JP20K10449]
This study synthesized a novel ciprofloxacin derivative that exhibited dual inhibition of topo I and topo II enzymes, leading to the suppression of cancer cell proliferation, migration, and colony formation. It also induced apoptotic and necro-apoptotic pathways, activating the cleaved caspase 3, RIPK1, RIPK3, and MLKL proteins.
Fluoroquinolones (FQs) are synthetic broad-spectrum antimicrobial agents that have been recently repurposed to anticancer candidates. Designing new derivatives of FQs with different moieties to target DNA topoisomerases could improve their anticancer efficacy. The present study aimed to synthesize a novel ciprofloxacin derivative, examine its anticancer activity against HepG2 and A549 cancer cells, and investigate the possible molecular mechanism underlying this activity by examining its ability to inhibit the topo I/II activity and to induce the apoptotic and necro-apoptotic pathways. Molecular docking, cell viability, cell migration, colony formation, cell cycle, Annexin V, lactate dehydrogenase (LDH) release, ELISA, and western blotting assays were utilized. Molecular docking results showed that this novel ciprofloxacin derivative exerted dual topo I and topo II binding and inhibition. It significantly inhibited the proliferation of A549 and HepG2 cancer cells and decreased their cell migration and colony formation abilities. In addition, it significantly increased the % of apoptotic cells, caused cell cycle arrest at G2/M phase, and elevated the LDH release levels in both cancer cells. Furthermore, it increased the expression of cleaved caspase 3, RIPK1, RIPK3, and MLKL proteins. This novel ciprofloxacin derivative exerted substantial dual inhibition of topo I/II enzyme activities, showed antiproliferative activity, suppressed the cell migration and colony formation abilities for A549 and HepG2 cancer cells and activated the apoptotic pathway. In addition, it initiated another backup deadly pathway, necro-apoptosis, through the activation of the RIPK1/RIPK3/MLKL pathway.
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