A kinetically inert platinum antitumor agent overcomes mutant p53-driven chemoresistance via oxidative...

Therapy resistance is a complex and multifaceted pathological phenomenon, often driven by mutations in the p53 tumor suppressor gene. This ultimately causes tumor recurrence thereby adversely affecting patient prognosis. Therefore, development of effective chemotherapeutic agents that simultaneously inhibit tumor proliferation and overcome resistance mechanisms is of paramount importance. Recently, we identified Compound 4, a kinetically inert platinum-based antitumor agent capable of bypassing platinum resistance while exhibiting minimal nephrotoxicity. However, its potency in resistance scenario is still not investigated. Herein we evaluate the efficacy of Compound 4 against platinum-resistant cancers driven by mutant p53, using engineered p53-null ovarian (SKOV3) and gastric (KATOIII) cancer cell lines expressing hot-spot p53 mutants (p53^mut) as well as patient derived tumor cells. While p53^mut expressing cells showed differential sensitivity towards platinum, Compound 4 demonstrated superior cytotoxicity, regardless of p53 mutational status. This enhanced efficacy was attributed to its ability to induce a sustained DNA damage. This was further observed to be compounded by a deficiency in DNA repair responses failing to elicit an effective damage response. Additionally, Compound 4 induced significant mitochondrial depolarization which led to generation of persistent oxidative stress-like environment. Compound 4-mediated oxidative stress plays a crucial role in mediating its robust cytotoxic effects, as pharmacological quenching of reactive oxygen species (ROS) with an antioxidant markedly reduced cell death and gamma H2AX levels. Taken together, these results underscore the potential of Compound 4 as a potent agent capable of overcoming platinum resistance by targeting cancer cells irrespective of their p53 mutational status.