Oncotarget

Research Papers:

Antitumor properties of Salvianolic acid B against triple-negative and hormone receptor-positive breast cancer cells via ceramide-mediated apoptosis

Wei Sha, Yanfei Zhou, Zhi-Qiang Ling, Guiqin Xie, Xiaowu Pang, Paul Wang and Xinbin Gu _

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Oncotarget. 2018; 9:36331-36343. https://doi.org/10.18632/oncotarget.26348

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Abstract

Wei Sha1, Yanfei Zhou2, Zhi-Qiang Ling3, Guiqin Xie1, Xiaowu Pang1, Paul Wang4,5,6 and Xinbin Gu1,5

1Departments of Oral Pathology, College of Dentistry, Howard University, Washington, D.C., USA

2TenGen Biomedical Co., Bethesda, Maryland, USA

3Zhejiang Cancer Hospital, Zhejiang Cancer Research Institute, Hangzhou, Zhejiang, China

4Department of Radiology, College of Medicine, Howard University, Washington, D.C., USA

5Cancer Center, Howard University, Washington, D.C., USA

6College of Science and Engineering, Fu Jen Catholic University, Taipei, Taiwan

Correspondence to:

Xinbin Gu, email: [email protected]

Keywords: salvianolic acid B; triple negative breast cancer; apoptosis; ceramides; glucosylceramide synthase

Abbreviations: Sal-B: Salvinolic acid B; TNBC: triple-negative breast cancer; ER-α: estrogen receptor α; HER2: human epidermal growth factor receptor-2

Received: August 19, 2018     Accepted: October 28, 2018     Published: November 20, 2018

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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