RESUMEN
Pharmacological reactivation of tumorsuppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a nonfunctional mutant p53 (mutp53). p53 plays a critical role in preserving genomic integrity and DNA fidelity through numerous biological processes, including cell cycle arrest, DNA repair, senescence and apoptosis. By contrast, nonfunctional mutp53 compromises the aforementioned genome stabilizing mechanisms through gain of function, thereby increasing genomic instability in human cancers. Restoring the functional activity of p53 using both genetic and pharmacological approaches has gained prominence in targeting p53mutated tumors. Thus, the present study aimed to investigate the reactivation of p53 in DNA repair mechanisms and the maintenance of genomic stability using PRIMA1MET/APR246 small molecules, in both MDAMB231 and MCF7 breast cancer cell lines, which carry mutp53 and wildtype p53, respectively. Results of the present study revealed that reactivation of p53 through APR246 led to an increase in the functional activity of DNA repair. Prolonged treatment of MDAMB231 cells with APR246 in the presence of cisplatin led to a reduction in mutational accumulation, compared with cells treated with cisplatin alone. These findings demonstrated that APR246 may act as a promising small molecule to control the genomic instability in p53mutated tumors.