The Anti-proliferation Effects Of CS055Alone Or In Combination With Paclitaxel/Carboplatin In Multiple Breast Cancer Cell Lines And Its Influence On The Expression Of ER In ERα Negative Breast Cancer Cells

Acetylation of histones and other nuclear proteins plays an important role in cancer development and progression. Histone deacetylases(HDACs) which remove the acetyl group of the ε-amino groups of lysine residues in the N-terminal extension of the core histones, play crucial roles in numerous biological processes, mainly through their repressive influence on transcription, and thus become very influential and powerful targets for many diseases recently, especially on cancer. Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anticancer agents. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models,and may have synergistic effects with chemotherapy.In breast cancer. Tumor expression of estrogen receptors a (ER a) is important as a marker of prognosis and mostly as a predictor of response to endocrine therapy. In fact, the loss of ERa expression leads to unresponsiveness to antihormone treatment. In a significant fraction of breast cancers, this loss of expression is a result of epigenetic mechanisms, such as DNA methylation and histone deacetylation Previous studies have shown that pharmacologic inhibition of these mechanisms using DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors results in expression of functional ERa mRNA and protein. CS055is a novel synthetic HDAC inhibitor. We investigate the anti-cancer activity of CS055in multiple breast cancer cells, and in combination with pactitaxel/carboplatin in triple-negative breast cancer cells, the influence on the expression of ER in ER a negative breast cancer cells. CS055effects on the proliferation of human breast cancer cell lines were tested using MTS assays. Changes in ER were examined by western blotting and realtime-PCR. Results show CS055inhibited proliferation of multiple breast cancer cell lines (BT-549,MDA-MB-468,MCF-7, MDA-MB-231,MDA-MB-435,T-47D), especially ERa negative breast cancer cells (MDA-MB-435and BT-549). Its value of GI50ranged from0.91to7.9μM. Combination of CSO55and pactitaxel/carbop latin exerted superior efficacy against triple-negative human breast cancer cells (Hs578T), compared with chemotherapy alone, but in MDA-MB-231cells, There was no difference. Realtime-PCR and Westernblot test indicated CS055increased the expression of ERβ in ERa-negative human breast cancer cells(BT-549), but not ERa. CS055restored response to tamoxifen in BT-549cells. Collectively, these findings indicated that CS055may be a potent anti-cancer agent against breast cancer. CS055increased the anti-tumor effects of pactitaxel and carboplatin in triple-negative breast cancer in vitro. The combination of CS055and pactitaxel/carboplatin may have therapeutic potential in the treatment of triple-negative breast cancer. CS055sensitized ERa-negative breast cancer cells to tamoxifen treatment possibly by upregulating ERβ activity, may provide a new treatment approach for ERa-negative breast cancer patients in clinical practice.