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Genistein Enhances the Radiosensitivity of Breast Cancer Cells via G2/M Cell Cycle Arrest and Apoptosis
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, Gansu, China
Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, Gansu, China
University of Chinese Academy of Sciences, Beijing 100049, China
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 18 September 2013; in revised form: 14 October 2013 / Accepted: 18 October 2013 / Published: 24 October 2013
Abstract: The aim of the present study was to investigate the radiosensitizing effect of genistein, and the corresponding mechanisms of action on breast cancer cells with different estrogen receptor (ER) status. Human breast cancer cell lines such as MCF-7 (ER-positive, harboring wild-type p53) and MDA-MB-231 (ER-negative, harboring mutant p53) were irradiated with X-rays in the presence or absence of genistein. Cell survival, DNA damage and repair, cell cycle distribution, cell apoptosis, expression of proteins related to G2/M cell cycle checkpoint and apoptosis were measured with colony formation assays, immunohistochemistry, flow cytometry and western blot analysis, respectively. Genistein showed relatively weak toxicity to both cell lines at concentrations in the range of 5–20 μM. Using the dosage of 10 μM genistein, the sensitizer enhancement ratios after exposure to X-rays at a 10% cell survival (IC10) were 1.43 for MCF-7 and 1.36 for MDA-MB-231 cells, respectively. Significantly increased DNA damages, arrested cells at G2/M phase, decreased homologous recombination repair protein Rad51 foci formation and enhanced apoptotic rates were observed in both cell lines treated by genistein combined with X-rays compared with the irradiation alone. The combined treatment obviously up-regulated the phosphorylation of ATM, Chk2, Cdc25c and Cdc2, leading to permanent G2/M phase arrest, and up-regulated Bax and p73, down-regulated Bcl-2, finally induced mitochondria-mediated apoptosis in both cell lines. These results suggest that genistein induces G2/M arrest by the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway and ultimately enhances the radiosensitivity of both ER+ and ER- breast cancer cells through a mitochondria-mediated apoptosis pathway.
Keywords: breast cancer cells; radiosensitivity; genistein; G2/M arrest; apoptosis
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Liu, X.; Sun, C.; Jin, X.; Li, P.; Ye, F.; Zhao, T.; Gong, L.; Li, Q. Genistein Enhances the Radiosensitivity of Breast Cancer Cells via G2/M Cell Cycle Arrest and Apoptosis. Molecules 2013, 18, 13200-13217.
Liu X, Sun C, Jin X, Li P, Ye F, Zhao T, Gong L, Li Q. Genistein Enhances the Radiosensitivity of Breast Cancer Cells via G2/M Cell Cycle Arrest and Apoptosis. Molecules. 2013; 18(11):13200-13217.
Liu, Xiongxiong; Sun, Chao; Jin, Xiaodong; Li, Ping; Ye, Fei; Zhao, Ting; Gong, Li; Li, Qiang. 2013. "Genistein Enhances the Radiosensitivity of Breast Cancer Cells via G2/M Cell Cycle Arrest and Apoptosis." Molecules 18, no. 11: 13200-13217.