Apoptosis induction in human breast cancer cell lines by synergic effect of raloxifene and resveratrol through increasing proapoptotic genes.

ABSTRACT

AIMS: Breast cancer is the most common cancer of women. The aim of this study was to investigate the synergic effect of raloxifene (Ral) and resveratrol (Res) on apoptosis of breast cancer cell lines (MCF7 and MDA-MB-231). MAIN METHODS: Cells were treated with Ral and Res alone and in combination. Cell viability (MTT assay), apoptosis (TUNEL assay) and nitric oxide (NO) production (Griess method) were investigated. Expression of proapoptotic gene (Bax and p53), anti-apoptotic gene (Bcl2) and caspases-3, caspase -8 were evaluated. One-way ANOVA test was used for data analysis. KEY FINDINGS: The viabilities of MCF7 and MDA-MB-231 cells treated by Ral (1 µM) and Res (20 µM) decreased significantly (p = 0.000) and their synergic use showed more reduction. Nitric oxide production by MCF7 and MDA-MB-231 cells exposed upon each drug alone and in combination showing a significant reduction (p = 0.000). There was also an increase in apoptosis in the cells treated with combination use of Ral and Res in both cell lines. Moreover, reduced expression of Bcl2 and increased expression of Bax and p53 genes were observed. SIGNIFICANCE: The synergic effects of Ral and Res through increased ratio of Bcl2/Bax and expressions of p53, caspase-3 and caspase-8 genes indicating a better therapeutic effect on breast cancer cells relative to each drug alone. Combination of Res and Ral via increased expression of apoptotic genes including Bax, p53 and caspase-3 and caspase-8 is able to promote apoptosis as a mitochondrial dependent pathway in MCF7 and MDA-MB-231. The synergic effect was more potent in MCF7 estrogen receptor positive cell line.