A Novel Cisplatin-Based Prodrug Inhibits Lysine Deacetylases, Suppresses Nucleotide Excision Repair, and Overcomes Resistance

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage, but drug resistance severely limits its efficacy and use. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcription regulation. The combination of cisplatin and KDAC inhibitors has shown promise in improving treatment efficacy. This improved efficacy has been attributed to increased drug sensitivity due to higher chromatin accessibility, however, this hypothesis has not been validated. In this study, we synthesized a novel Pt(IV) derivative, cct-[Pt(NH3)2Cl2(VPA)(PhB)] (cPVP), which combines cisplatin and two KDAC inhibitors, phenyl butyrate and valproic acid. This triple-action prodrug enabled the simultaneous targeting of multiple cancer-related pathways. Compared to cisplatin, cPVP exhibited significantly enhanced damage formation and cytotoxicity. High-resolution mapping of cisplatin damage and repair, however, does not attribute the enhanced damage sensitivity to chromatin accessibility, but rather to increased drug uptake and inhibition of nucleotide excision repair. Moreover, cPVP treatment increased survival in a mouse mesothelioma model, and prevented the development of resistance to both cisplatin and itself in cancer cells. Our findings shed new light on the effect of KDAC inhibition on cisplatin treatment, and suggest that cPVP could serve as a promising alternative to cisplatin in the clinic.