Ketamine Induces Mitochondrial Fission and Dysfunction in Cervical Cancer Cells via RhoA‐Dependent DRP‐1 Activation

Abstract

Mitochondrial fragmentation, which is closely linked to mitochondrial dysfunction, has emerged as a critical treatment target for cervical cancer. Ketamine, a well-known anesthetic, has shown potential in cancer therapy by inducing cytotoxicity, impairing mitochondrial function, and promoting apoptosis in tumor cells. Notably, the regulatory role of ketamine in mitochondrial network dynamics remains unexplored in current scientific literature. In this study, we demonstrated that ketamine exerts significant cytotoxic effects on C33A cervical cancer cells, as evidenced by dose-dependent increases in γ-glutamyl transpeptidase (GGT) levels and lactate dehydrogenase (LDH) release, accompanied by a corresponding reduction in cell viability. At 100 μM, ketamine induces mitochondrial dysfunction, characterized by decreased Complex IV activity, mitochondrial membrane potential (MMP), and ATP production, along with mitochondrial fragmentation. Mechanistically, ketamine upregulates mitochondrial p-Drp1 levels without altering total DRP-1 and enhances the expression of CaMK II and RhoA, but not Rac1/Cdc42. Inhibition of RhoA, but not CaMK II, attenuates ketamine-induced mitochondrial DRP-1 activation, fragmentation, and dysfunction, suggesting that RhoA is a key mediator. These findings highlight ketamine's potential as a therapeutic agent targeting mitochondrial dynamics in cervical cancer.