RG108-Pt(IV) Prodrug as a Potential Antitumor Agent with Hearing Protection Effects in Squamous Cell Carcinoma of the Head and Neck

This study developed a novel series of Pt(IV) prodrugs derived from the hearing-protective ligand RG108, including mono- and di-substituted cisplatin and oxaliplatin derivatives, to achieve high therapeutic efficacy with reduced toxicity. Compound 4 emerged as a standout candidate, demonstrating remarkable anti-tumor activity in FADU cells with an IC50 value exceeding 500-fold that of cisplatin. It potently induced apoptosis, suppressed migration, and exhibited robust in vivo anti-tumor efficacy. Mechanistically, the compound was found to enhance platinum accumulation in tumor cells via the EZH2/SLC47A2 regulatory axis, marking the first introduction of this pathway into tetravalent platinum drug research. Notably, the synthesized derivatives significantly mitigated platinum-associated ototoxicity, as evidenced by preserved cochlear hair cell viability, stabilized auditory brainstem response thresholds, and intact cochlear basement membrane morphology, thereby overcoming the hearing loss limitations of conventional platinum chemotherapy. This work establishes a pioneering framework for designing dual-functional platinum-based agents that synergize anti-tumor potency with organoprotective properties, offering both theoretical insights and translational potential.