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.
Highlights
Breast cancer is the most common cancer in women and the second highest lethal form of cancer in the United States [1]
These findings indicate that Salvinolic acid B (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
The results showed that Sal-B had a high potency against Triple-negative breast cancer (TNBC), which was mediated by inhibiting the tumor cell growth and enhancing the ceramide-mediated apoptosis through Glucosylceramide synthase (GCS)-catalyzed ceramide glycosylation
Summary
Breast cancer is the most common cancer in women and the second highest lethal form of cancer in the United States [1]. Studies have shown that the incidence of breast cancer has been gradually decreasing in the last two decades, women in the United States still have a one in eight chance of developing breast cancer in their lifetime [2]. About one third of breast cancer is triple-negative (TNBC), presenting the lack of expression www.oncotarget.com of estrogen receptor α (ER-α), progesterone receptor, and human epidermal growth factor receptor-2 (HER2) [3]. Due to the poor response to anti-hormonal treatment and chemotherapeutics, TNBC is considered an aggressive form of breast cancer [3]. The commonly used therapeutic agents for breast cancer including doxorubicin have little success in treating patients with TNBC [4]. The cardiotoxicity risk of doxorubicin limits its clinical applications [5, 6]
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