1. Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada.
2. School of Life Science, Foshan University, Foshan, Guangdong 528000, P.R. of China.
3. Entry-Exit Inspection and Quarantine Bureau, Nanhai, Guangdong 528200, P.R. of China.
Sphingosine-1-phosphate (S1P) is an important sphingolipid metabolite regulating key physiological and pathophysiological processes such as cell growth and survival and tumor angiogenesis. Significant research evidence links elevated cellular S1P concentration to cancer cell proliferation, migration and angiogenesis. Physiological levels of S1P are tightly regulated and maintained at the low nanomolar level. In cancer, S1P may exist well beyond the low nanomolar level. Recently, we reported that S1P selectively induces cell apoptosis of the breast cancer MCF7 cell line at concentrations higher than 1 µM and co-administration of 1 µM S1P significantly increased the cytotoxicity of chemotherapy drug docetaxel. In this study, we show that S1P caused minor increases in cell proliferation or apoptosis, in a concentration-dependent manner, yet co-administration of 10 µM S1P exhibited a significant synergistic effect with chemotherapy drugs docetaxel, doxorubicin and cyclophosphamide. S1P increased the cytotoxic potential of each drug by 2-fold, 3-fold, and 10-fold, respectively, against the breast cancer metastatic cell line MDA-MB-361. This synergism may suggest improved anticancer drug therapy by co-administration of exogenous S1P.
Keywords: Brain-metastasized breast cancer, apoptosis, cytotoxicity, chemotherapy, sphingosine-1-phosphate.