P53 reactivating small molecule PRIMA‑1MET/APR‑246 regulates genomic instability in MDA‑MB‑231 cells.

Abstract

Pharmacological reactivation of tumor‑suppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a non‑functional 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, non‑functional 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 p53‑mutated tumors. Thus, the present study aimed to investigate the reactivation of p53 in DNA repair mechanisms and the maintenance of genomic stability using PRIMA‑1MET/APR‑246 small molecules, in both MDA‑MB‑231 and MCF‑7 breast cancer cell lines, which carry mutp53 and wild‑type p53, respectively. Results of the present study revealed that reactivation of p53 through APR‑246 led to an increase in the functional activity of DNA repair. Prolonged treatment of MDA‑MB‑231 cells with APR‑246 in the presence of cisplatin led to a reduction in mutational accumulation, compared with cells treated with cisplatin alone. These findings demonstrated that APR‑246 may act as a promising small molecule to control the genomic instability in p53‑mutated tumors.