CDDO-imidazolide induces DNA damage, G2/M arrest and apoptosis in BRCA1-mutated breast cancer cells.

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.

• Authors: Eun-Hee Kim, Chu-Xia Deng, Michael B Sporn, Karen T Liby
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 3 Pg. 425-34 (Mar 2011) ISSN: 1940-6215 [Electronic] United States
• PMID: 21372041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
• Antineoplastic Agents
• Enzyme Inhibitors
• Imidazoles
• Reactive Oxygen Species
• Oleanolic Acid
• imidazole

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Breast Neoplasms (genetics, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• DNA Damage
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (metabolism)
• Genes, BRCA1
• Humans
• Imidazoles (pharmacology)
• Mice
• Mutation
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Reactive Oxygen Species (metabolism)