Cinoplatin: An Efficient Platinum(IV) Prodrug Effective in Inhibiting the Growth of Cervical Cancer

Abstract

Platinum(IV) prodrugs are emerging as promising anticancer agents due to their potential to improve cellular uptake, selectively target tumors, and reduce the systemic toxicity of their parental Pt(II) drugs. In this study, we synthesized a dual-action Pt(IV) complex, cinoplatin, by anchoring 3,4-(methylenedioxy)cinnamic acid at the axial position of oxoplatin. Cellular studies demonstrated that cinoplatin exhibited markedly higher sensitivity toward cervical carcinoma cells compared to other tested cancer cell lines, indicating a degree of tumor-type selectivity. Subcellular distribution analysis revealed that the complex preferentially accumulates in the cytoplasm, with minor fractions localized in the nucleus and mitochondria. Mechanistic analyses showed that nuclear localization induces significant DNA damage, as evidenced by elevated γ-H2AX and p53 levels, while mitochondrial targeting disrupts membrane potential, elevates reactive oxygen species, and impairs mitochondrial respiration and glycolysis. These combined effects trigger robust apoptosis in HeLa cells. Collectively, the high cellular uptake and dual subcellular targeting of cinoplatin highlight its mechanistically distinct cytotoxic profile, emphasizing the potential of dual-action Pt(IV) complexes to enhance anticancer efficacy.