Platinum(IV) oxaliplatin analog containing axial benzoate ligands induces mitochondrial hyperpolarization and caspase-dependent apoptosis in pancreatic cancer cell models.

This study investigates the molecular mechanisms underlying the antiproliferative effects of the platinum(IV) complex trans-[Pt(OBz)(O,C-10-BzODA)(1R,2R-DACH)] (complex 1; OBz = benzoate, 10-BzODA = 10-benzoyloxy-2-decenoate, DACH = diaminocyclohexane) in pancreatic cancer cell models. Initial findings revealed that complex 1 exhibits substantial antiproliferative activity, positioning it as a promising therapeutic agent for pancreatic cancer, where effective treatment options remain limited. Notably, complex 1 demonstrates significantly greater efficacy compared to platinum(II) drugs, such as cisplatin and oxaliplatin, with IC values in the low micromolar range across various pancreatic cancer cell lines. Mechanistic studies suggest that complex 1's enhanced activity is attributed to the axial benzoate ligands, which differentiate it from its platinum(II) analog. Complex 1 accumulates intracellular platinum without undergoing reduction in the extracellular environment, and it induces mitochondrial hyperpolarization. This effect is reminiscent of free sodium benzoate but occurs at a much lower extracellular concentration, indicating the crucial role of the benzoate ligands in modulating mitochondrial function. Furthermore, complex 1 triggers caspase-dependent apoptosis in cancer cells and is also effective in 3D tumor cell models, highlighting its potential as an effective anticancer agent. Thus, this work presents a Pt(IV) prodrug bearing benzoate axial ligands that exhibit distinctive chemical and biological behavior compared with previously reported Pt(IV) prodrugs. In conclusion, the unique properties of complex 1, driven by its benzoate ligands, suggest that Pt(IV) complexes represent a promising approach for the development of targeted chemotherapeutic agents for the treatment of pancreatic cancer.