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.
Highlights
Female breast cancer is the most common disease in women
Genistein inhibited the proliferation of the two kinds of breast cancer cells slightly when its concentration was below 20 μM
The results definitely suggest that genistein-exacerbated G2/M arrest and subsequent apoptosis-related cell death are two main factors for enhancing the radiosensitivity of both MCF-7 and MDA-MB-231 cell lines
Summary
Female breast cancer is the most common disease in women. 500,000 deaths per year occur from breast cancers worldwide [1,2]. The incidence of breast cancers is expected to rise in the coming years and the age of patients is tending to be younger [3]. In class 1, breast cancer cells (such as MCF-7) are ER-positive, hormone-dependent, responsive to estrogen and successfully treated with anti-hormones such as tamoxifen. In class 2, breast cancer cells (such as 21PT) are ER-positive, hormone-independent and non-responsive to anti-hormones. Class 3 breast cancer cells (such as MDA-MB-231) are ER-negative, hormone-independent, hormone non-responsive and high-grade malignant tumors. Treatment options for breast cancer patients are limited to conventional cytotoxic chemotherapy, which is not effective against high-grade malignant tumors, and there are serious side effects [5,6,7]. To improve the local control and survival rate, radiation therapy combined with radiosensitizing reagents is one of the most effective treatments against breast cancers
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