期刊
CLINICAL CANCER RESEARCH
卷 17, 期 9, 页码 2830-2841出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-3168
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资金
- A. P. Moller Foundation for the Advancement of Medical Science
- Novo Nordisk Foundation
- Danish Cancer Society
- Danish Medical Research Council
- Aase and Ejnar Danielsen Foundation
- University of Copenhagen
- VFK Krebsforschung gGmbH in Germany
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. Clin Cancer Res; 17(9); 2830-41. (C)2011 AACR.
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