Unveiling the chemotherapeutic potential of two platinum(IV) complexes in skin cancer: in vitro and in vivo Insights

The present study investigates the chemotherapeutic potential of two platinum (IV) complexes, P-PENT and P-HEX, against skin cancer in vitro and in vivo . Both complexes exhibited potent cytotoxicity against HaCaT-II-4 cells with IC 50 values of 0.8 ± 0.08 μM and 1.3 ± 0.16 μM respectively, while demonstrating 8-10-fold selectivity compared to mesenchymal stem cells (MSCs). Western blot analysis revealed significant modulation of key apoptotic and survival pathways, including upregulation of Bax/Bcl2 ratio, cleaved caspase 3, and cytochrome c , suggesting induction of intrinsic apoptosis. The complexes also inhibited PI3K and MAPK pathways, as evidenced by decreased p-AKT/AKT and p-ERK/ERK ratios. Flow cytometry confirmed significant apoptotic cell death. Both complexes also increased reactive oxygen species production. In a DMBA/TPA-induced skin carcinogenesis mouse model, both complexes significantly suppressed tumor growth at doses considerably lower than the maximum tolerated dose, with no detectable toxicity. A dose escalation study in BALB/c mice showed that P-PENT and P-HEX were approximately 5-fold and 4-fold more tolerated than cisplatin, respectively. In conclusion, the present study provides evidence that P-PENT and P-HEX may have the characteristics of an effective and potentially safe anti-tumor drug that could be used in skin cancer treatment. • Two platinum (IV) complexes exhibit potent cytotoxicity against HaCaT-II-4 skin cancer cells. • Both complexes show 8–10 fold selectivity for cancer cells compared to mesenchymal cells. • Cell death is induced via intrinsic apoptosis and inhibition of PI3K and MAPK pathways. • Elevated ROS production enhances the compounds' cytotoxic properties. • In a skin cancer mouse model, tumor growth is suppressed without any detected toxicity.