Abstract 5676: Effects of resveratrol on paclitaxel-sensitive and -resistant triple negative breast cancer cells

Treatment of drug-resistant cancer cells remains a difficult problem in cancer therapy because most resistant cells can pump out drugs or upregulate other survival pathways to bypass a targeted therapy. The polyphenol natural compound, resveratrol, has been shown to inhibit cell growth of multiple cancer types, but it is not cytotoxic to normal cells. However, the effects of resveratrol in triple negative breast cancer cells (estrogen receptor-, progesterone receptor-, and HER2-negative) as well as cancers that are resistant to the common cancer drug, paclitaxel, are not well understood. In this study, the effects of resveratrol were investigated in the triple negative breast cancer cell line MDA-MB-231 as well as a novel MDA-MB-231 derived paclitaxel-resistant line generated in our laboratory. Assays for cell proliferation, apoptosis, and protein expression changes related to apoptosis and survival were utilized in order to determine the differential effects of resveratrol on the parental and resistant cell lines. At lower (< 10 μM) concentrations, resveratrol induced cell proliferation in both cell lines, consistent with other studies demonstrating lifespan extension of normal cells with resveratrol treatment. On the other hand, after treatment with 10-100 μM concentrations of resveratrol, both cell lines exhibited a reduction in cell proliferation, with the paclitaxel-resistant cells to a greater extent. In addition, resveratrol decreased the ability of both cell lines to form colonies when plated at low density (an indication of reduced cell survival capacity). Furthermore, resveratrol treatment increased the amount of DNA fragmentation associated with apoptosis compared to untreated controls in both cell lines, but the paclitaxel resistant cells were more sensitive to resveratrol treatment than the parental cells. By protein expression analyses, we observed that in both the parental and paclitaxel-resistant cell lines, resveratrol may be acting through NAD-dependent deacetylase sirtuin (SIRT1) activity by decreasing the expression of the inhibitor-of-apoptosis protein, surviving and increasing the activator-of-apoptosis, caspase 3. Based on these data, we propose that resveratrol can inhibit proliferation and induce apoptosis in triple negative breast cancer cells, including paclitaxel-resistant cells. These results provide rationale for the use of resveratrol as an important starting point for the development of a novel anti-cancer agent for drug res