Antipsychotic Drug Cariprazine Induces Distinct Cell Death Mechanisms in HeLa and HCT116 Cells as a Potential Inhibitor of Qi-Site of Cytochrome bc1 Reductase

<b>Background/Objectives</b>: Cariprazine (CAR), an atypical antipsychotic drug, exhibits potent anticancer activity; however, its mechanism of action remains unclear. <b>Methods</b>: We conducted a comparison of CAR-induced cell death mechanism in HeLa and HCT116 cancer cells and explored its potential role as a Qi-site inhibitor of cytochrome bc1 reductase (complex III). <b>Results</b>: CAR induced a dose-dependent cytotoxic effect and triggered apoptosis in both cell lines; however, the mitochondrial responses were distinctively different. HeLa cells exhibited significant mitochondrial membrane depolarization, significant cytochrome c release, a strong increase in the Bax/Bcl-2 ratio, elevated caspase-3 activation, and notable S phase arrest along with autophagy induction, indicating that mitochondria-driven apoptosis occurred rapidly. In contrast, HCT116 cells showed moderate mitochondrial dysfunction, moderate cytochrome c release, enhanced suppression of Akt signaling, and significant G0/G1 phase arrest, which are consistent with a slower and mixed apoptotic response. The findings from molecular docking studies predicted that CAR had stable binding at the Qi site and showed interactions at the Qi site that were comparable to those of antimycin A, thereby suggesting its possible inhibitory effect on complex III. <b>Conclusions</b>: The results from our study indicate the engagement of CAR-activated apoptotic pathways that are specific to different types of cancer cells, and hence suggest that CAR may act as a new anticancer drug by potentially directing its action towards the mitochondrial Qi-sites of complex III.