PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53.

Abstract

PURPOSE:

Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations.

EXPERIMENTAL DESIGN:

The therapeutic effect of PRIMA-1(Met)/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1(Met)/APR-246 was further evaluated in two different SCLC xenograft models.

RESULTS:

PRIMA-1(Met)/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1(Met)/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1(Met)/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1(Met) after i.v. injection in SCLC mouse models with no apparent toxicity.

CONCLUSION:

This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1(Met)/APR-246 for the treatment of SCLC.

• Authors: Roza Zandi, Galina Selivanova, Camilla Laulund Christensen, Thomas Alexander Gerds, Berthe Marie Willumsen, Hans Skovgaard Poulsen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 9 Pg. 2830-41 (May 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21415220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antineoplastic Agents
• Mutant Proteins
• Quinuclidines
• eprenetapopt

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Progression
• Genes, p53
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Male
• Mice
• Mice, Nude
• Mutant Proteins (genetics, metabolism)
• Quinuclidines (pharmacology, therapeutic use)
• Small Cell Lung Carcinoma (drug therapy, genetics, pathology)
• Time Factors
• Xenograft Model Antitumor Assays