Prima-1 induces apoptosis in bladder cancer cell lines by activating p53

Abstract

OBJECTIVES:Bladder cancer represents 3% of all carcinomas in the Brazilian population and ranks second in incidence among urological tumors, after prostate cancer. The loss of p53 function is the main genetic alteration related to the development of high-grade muscle-invasive disease. Prima-1 is a small molecule that restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Our aim was to investigate the ability of Prima-1 to induce apoptosis after DNA damage in bladder cancer cell lines.METHOD:The therapeutic effect of Prima-1 was studied in two bladder cancer cell lines: T24, which is characterized by a p53 mutation, and RT4, which is the wild-type for the p53 gene. Morphological features of apoptosis induced by p53, including mitochondrial membrane potential changes and the expression of thirteen genes involved in apoptosis, were assessed by microscopic observation and quantitative real-time PCR (qRT-PCR).RESULTS:Prima-1 was able to reactivate p53 function in the T24 (p53 mt) bladder cancer cell line and promote apoptosis via the induction of Bax and Puma expression, activation of the caspase cascade and disruption of the mitochondrial membrane in a BAK-independent manner.CONCLUSION:Prima-1 is able to restore the transcriptional activity of p53. Experimental studies in vivo may be conducted to test this molecule as a new therapeutic agent for urothelial carcinomas of the bladder, which characteristically harbor p53 mutations.

p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells

“…Curiously, up-regulation of MDM2 by activated p53 (36, 37) did not occur in PRIMA-1-treated MDA-MB-231cells. This finding was also observed for p53 mutants in bladder cancer cells (61) and indicates that the mutant p53 recovery promoted by PRIMA-1 might not recover all of WTp53 functions. Wiech et al (62) report the formation of "pseudo-aggregates" of mutant p53, MDM2, and HSP70 that form amyloid-like structures.…”

p53 Family and Cellular Stress Responses in Cancer

“…PRIMA-1 (p53 reactivation and induction of massive apoptosis) is a pro-drug ( 220 ). The molecule effectively induces apoptosis in bladder cancer cell lines ( 221 ). Later, PRIMA-1 MET (APR-246), a compound that bears great structural similarities to PRIMA-1, but has higher activity than its predecessor, was discovered ( 222 ).…”

MicroRNA-29a plays a prominent role in PRIMA-1Met-induced apoptosis in ovarian cancer cells

“…Studies have shown that PRIMA-1 Met is more effective in cancer cells expressing mutant p53 than wild-type p53 or null cells [16,34], while several studies have shown that PRIMA-1 Met exhibits cytotoxic effects independent of the p53 mutation status [35][36][37][38]. It was reported that PRIMA-1 Met has sufficient activity to suppress growth in epithelial ovarian cancer cells, regardless of the mutation status of p53 [30].PRIMA-1 was shown to trigger apoptosis by altering the expression of p53 downstream genes such as p53 upregulated modulator of apoptosis (PUMA), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) and apoptosis regulator BAX, also known as bcl-2-like protein 4 in the mutant p53 bladder cancer cell line [39]. PRIMA-1 induces apoptosis by promoting the activation of proapoptotic signaling pathways and inhibiting JNK cell viability in mutant p53 breast cancer cells [40].In this study, PRIMA-1 Met was shown to cause a significant reduction in cell viability and increased apoptosis in ovarian cancer cells carrying both wild-type p53 and mutant p53.…”