Cumulative effects of ciprofloxacin and pilocarpine on cytotoxicity and G0 phase arrest in hepatoma-derived Hep G2 cell line. (21st June 2020)

• Record Type: Journal Article
• Authors: Sadeghi, Leila; Maleki, Somaiyeh; Dehghan, Gholamreza
• Is Part Of: Journal of pharmacy and pharmacology. Volume 72:Number 10(2020)
• Page Start: 1383
• Page End: 1393
• Publication Date: 2020-06-21
• Subjects: Ca2+ homoeostasis -- cell cycle arrest -- combined drug -- DNA double-strand breaks -- mitochondrial-dependent apoptosis -- synergic effect; Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.13318
• Languages: English
• ISSNs: 0022-3573

Abstract

Abstract: Objectives: Uncontrolled cell proliferation was caused by multiple deficient pathways that inhibition of one pathway may result to activate an alternative pathway. Therefore, combination of drugs which targeted multiple pathways could be beneficial to overcome drug resistance. Ciprofloxacin (CPF) cytotoxicity was widely investigated on cancer cell lines, and results revealed hepatoma-derived Hep G2 cells are relatively resistant. So, this study aimed to increase CPF cytotoxicity by rational design of a supplement which targeted Ca 2+ homoeostasis as major hub in unchecked proliferation. Methods: Cells were treated by CPF and/or pilocarpine (PILO), and cell cycle distribution, caspases activity and regulatory proteins were evaluated. Key findings: MTT and flow cytometry analysis confirmed administration of CPF + PILO causes more cytotoxicity. CPF-exposed cells accumulated in S phase due to DNA damages while PILO + CPF imposed G0 stage arrest through cyclin D1 and P-Akt downregulation. Caspase 8 was activated in cells treated by CPF but accompaniment of PILO with CPF led to activation of caspase 9, 8 and 3 and ROS overproduction. Conclusions: Ciprofloxacin imposed mitochondrial-independent apoptosis while PILO + CPF caused mitochondrial-dependent and independent apoptosis simultaneously. Consequently, coadministration of PILO and CPF causes intense cytotoxic effects through targeting the mitochondria, DNA gyrase enzyme and other unknown mechanisms.