Tranilast enhances the anti-tumor effects of tamoxifen on human breast cancer cells in vitro

Background: Tamoxifen is the most widely used anti-estrogen for the treatment of breast cancer. Studies show that the combination therapy with other substances that helps the activity of tamoxifen. The objective of this study was to evaluate the effect of tamoxifen when used in combination with tranilast on human breast cancer cells. Results: Two MCF-7 and MDA-MB-231 human breast cancer cell lines were treated with tamoxifen and/or tranilast. The cell viability and cytotoxicity was assessed using MTT and LDH assays; the apoptotic effects were examined by TUNEL assay, acridine orange/ethidium bromide staining and DNA laddering, also the expression levels of bax and bcl-2 genes were detected by real-time RT-PCR. The mRNA expression of TGF-beta ligands and receptors examined using real-time RT-PCR and TGF-beta 1 protein secretion levels were also evaluated by ELISA assay. Inhibitory effect of these drugs on invasion and metastasis were tested by wound healing and matrigel invasion assay. We found that combination of these drugs led to a marked increase in growth and proliferation inhibition compared to either agent alone. Furthermore, bax and bcl-2 affected by tamoxifen and/or tranilast and resulted in a significant increase in bax and decrease in bcl-2 mRNA expression. In addition, treatment with tamoxifen and/or tranilast resulted in significant decreased in TGF-beta 1, 2, 3, TGF-beta RI and II mRNA and TGF-beta 1 protein levels while TGF-beta RIII mRNA level was increased and invasion was also inhibited. Conclusions: These findings indicate that tranilast, by synergistic effect, enhances the activity of tamoxifen and the TGF-beta pathway is a target for this combination therapy, therefore; we propose that this combined treatment may be suitable selection in prevention of breast cancer.