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PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines
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PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines
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Journal Article
PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines
2014
Overview
Summary
TP53
mutation is a common event in many cancers, including pancreatic adenocarcinoma, where it occurs in 50–70 % of cases. In an effort to reactivate mutant p53 protein, several new drugs are being developed, including PRIMA-1 and PRIMA-1
Met
/APR-246 (
p53 reactivation and induction of massive apoptosis
). PRIMA-1 has been shown to induce apoptosis in tumor cells by reactivating p53 mutants, but its effect in pancreatic cancer remains unclear. Here we investigated the effects of PRIMA-1 on cell viability, cell cycle and expression of p53-regulated proteins in PANC-1 and BxPC-3 (mutant
TP53
), and CAPAN-2 (wild-type
TP53
) pancreatic cell lines. Treatment with PRIMA-1 selectively induced apoptosis and cell cycle arrest in p53 mutant cells compared to CAPAN-2 cells. The growth suppressive effect of PRIMA-1 was markedly reduced in p53 mutant cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1 induced cell death. Moreover, treatment with the thiol group donor N-acetylcysteine completely blocked PRIMA-1-induced apoptosis and reinforced the hypothesis that thiol modifications are important for PRIMA-1 biological activity. In combination treatments, PRIMA-1 enhanced the anti-tumor activity of several chemotherapic drugs against pancreatic cancer cells and also exhibited a pronounced synergistic effect in association with the Mdm2 inhibitor Nutlin-3. Taken together, our data indicate that PRIMA-1 induces apoptosis in p53 mutant pancreatic cancer cells by promoting the re-activation of p53 and inducing proapoptotic signaling pathways, providing in vitro evidence for a potential therapeutic approach in pancreatic cancer.
Publisher
Springer US,Springer,Springer Nature B.V,Springer Verlag
Subject
/ Antineoplastic Agents - pharmacology
/ Aza Compounds - pharmacology
/ Biological and medical sciences
/ Boronic Acids - pharmacology
/ Bridged Bicyclo Compounds, Heterocyclic - pharmacology
/ Cell Survival - drug effects
/ Deoxycytidine - analogs & derivatives
/ Deoxycytidine - pharmacology
/ Drugs
/ Gastroenterology. Liver. Pancreas. Abdomen
/ Genes
/ Humans
/ Liver. Biliary tract. Portal circulation. Exocrine pancreas
/ Medicine
/ Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
/ Mutation
/ Oncology
/ Pancreatic Neoplasms - metabolism
/ Pharmacology. Drug treatments
/ Proteins
/ RNA, Small Interfering - genetics
/ Santé publique et épidémiologie
/ Studies
/ Tumor Suppressor Protein p53 - genetics
/ Tumor Suppressor Protein p53 - metabolism
/ Tumors
