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Abstract 2509: CDDO-Im induces DNA damage, G2/M arrest and apoptosis in BRCA1-mutated breast cancer cells

Department of Pharmacology, Dartmouth Medical School, Hanover, NH, USA.
Cancer Prevention Research (Impact Factor: 5.27). 03/2011; 4(3):425-34. DOI: 10.1158/1940-6207.CAPR-10-0153
Source: PubMed

ABSTRACT Breast cancer-associated gene 1 (BRCA1) protein plays important roles in DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide, CDDO-Im) is a promising anticancer and chemopreventive agent with potent antiproliferative and apoptotic activities against a wide variety of cancer types. However, the mechanisms responsible for the selective apoptotic effects of CDDO-Im in cancer cells remain elusive. In the present work, CDDO-Im induced G2/M arrest and apoptosis in BRCA1-mutated mammary tumor cell lines. Prior to the induction of apoptosis, CDDO-Im induced DNA damage and the phosphorylation of H2AX followed by activation of the DNA damage response. Moreover, CDDO-Im also induced the generation of reactive oxygen species (ROS), which is associated with the induction of DNA damage, in both mouse and human tumor cells containing a BRCA1 mutation. The inhibition of ROS generation by uric acid prevented the induction of DNA damage by CDDO-Im. Furthermore, treatment with CDDO-Im did not induce ROS in nonmalignant MCF-10A breast epithelial cells or in E18-14C-27 breast cancer cells with wild-type BRCA1 genes and was not cytotoxic to normal mouse 3T3 fibroblasts, highlighting a selective therapeutic potential of CDDO-Im for BRCA1-associated breast cancer cells. Altogether, our results show that CDDO-Im induces ROS and subsequent DNA damage, thereby facilitating the activation of the DNA damage checkpoint, G2/M arrest, and finally apoptosis in BRCA1-mutated cancer cells. The particular relevance of these findings to the chemoprevention of cancer is discussed. Cancer Prev Res; 4(3); 425-34. ©2011 AACR.

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    • "CDDO was shown to inhibit proliferation and induce peroxisome proliferator-activated receptor-c (PPAR-c) in human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer cells [29] [30]. CDDO-Im induced apoptosis in estrogen receptor negative and BRCA1 null breast cancer cells, by inducing reactive oxygen species (ROS), and subsequently DNA damage [31] [32]. In another study, CDDO-Im in combination with Gemini vitamin D analog, ABXL0124, potently inhibited HER2 or ErbB2 overexpressing breast cancer cells and repressed downstream signaling proteins, such as pErk1/2, pAKT, c- Myc, cyclin D1 and Bcl-2 [33]. "
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