Crizotinib-induced anti-cancer activity in human cervical carcinoma cells via ROS-dependent mitochondrial depolarization and induction of apoptotic pathway

Introduction: Cervical Cancer is one of the leading causes of mortality among women population worldwide. In spite of recurrent screening, vaccination, and chemotherapeutic interventions, combating cervical Cancer still remains a challenge. Crizotinib is a small molecule inhibitor that targets mesenchymal epithelial transition factor (c-MET) and has been successfully studied for its anti-cancer effects in non-small cell lung Cancer, pancreatic, gastric, renal, prostate, and breast carcinomas. Although c-MET is a well-known prognostic, diagnostic, and therapeutic target in cervical Cancer, anti-cancer properties of its inhibitor crizotinib against cervical carcinoma, has not been explored yet.

Methods: In the present study, the anti-cancer effects of crizotinib on cervical Cancer cells were evaluated using various in vitro cell-based assays, such as labelling drug-treated cells with MTT, H₂ DCFDA, Annexin V5-fluorescein isothiocyanate (FITC) antibody, JC-1, PI, and analysis using fluorescence-activated cell sorting (FACS).

Results: The molecule was found to effectively inhibit proliferation of cervical Cancer cells HeLa and SiHa with an IC₅₀ of 0.641 ± 0.0724 and 0.871 ± 0.104 μM, respectively, and induce Apoptosis in a dose-dependent manner. Further investigations showed that crizotinib-induced production of Reactive Oxygen Species (ROS) with increasing concentrations further resulted in mitochondrial membrane depolarization. However, the drug had no effect on cell cycle progression of HeLa and SiHa cells.

Conclusion: Thus, the study elucidates the cytotoxic effects of crizotinib in cervical Cancer cells by activation of ROS-dependent apoptotic pathway via mitochondrial depolarization. These findings will further aid the evaluation of other molecular mechanisms of crizotinib and would pave the way for its implication as a chemotherapeutic option in cervical Cancer.