Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options. It is urgent to develop new therapeutics against this disease. Salvinolic acid B (Sal-B) is a leading bioactive component of Salvia miltiorrhiza Bunge, a well-known Chinese medicine for treating various diseases without appreciable adverse effects. To understand the antitumor properties of Sal-B against TNBC, we analyzed its effects on the cell viability, cell cycle and apoptosis of triple-negative MDA-MB-231 cells with the hormone receptor-positive MCF-7 cells as the control. The in vitro analysis showed that Sal-B could significantly reduce the cell viability and suppress the proliferation of both MDA-MB-231 and MCF-7 cells with decreased cyclin B1 expression, but with no noticeable cell cycle phase change. In mouse models, Sal-B markedly inhibited the growth, decreased the PCNA expression, and increased the cell apoptosis of MDA-MB-231 tumor xenografts. To understand the antitumor mechanisms, we analyzed the expression levels of ceramides, and anti-apoptotic (Bcl-xL and survivin) and pro-apoptotic (caspase-3 and caspase-8) proteins. We found that Sal-B enhanced the ceramide accumulation and inhibited the anti-apoptotic protein expression. Interestingly, the ceramide accumulation was accompanied by decreased expression of glucosylceramide and GM3 synthases, two key enzymes regulating ceramide metabolism. These findings indicate that Sal-B exerts its antitumor effects at least partially by inducing the ceramide accumulation and ceramide-mediated apoptosis via inhibiting the expression of glucosylceramide and GM3 synthases, which was independent of estrogen receptor α. Sal-B appears to be a promising therapeutic agent against TNBC.
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