The opposite effects of doxorubicin on bone marrow stem cells versus breast cancer stem cells depend on glucosylceramide synthase.

Int J Biochem Cell Biol. 2012 Nov;44(11):1770-8.

Bhinge KN, Gupta V, Hosain SB, Satyanarayanajois SD, Meyer SA, Blaylock B, Zhang QJ, Liu YY.

Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71209, USA.

 

Abstract

Myelosuppression and drug resistance are common adverse effects in cancer patients with chemotherapy, and those severely limit the therapeutic efficacy and lead treatment failure. It is unclear by which cellular mechanism anticancer drugs suppress bone marrow, while drug-resistant tumors survive. We report that due to the difference of glucosylceramide synthase (GCS), catalyzing ceramide glycosylation, doxorubicin (Dox) eliminates bone marrow stem cells (BMSCs) and expands breast cancer stem cells (BCSCs). It was found that Dox decreased the numbers of BMSCs (ABCG2(+)) and the sphere formation in a dose-dependent fashion in isolated bone marrow cells. In tumor-bearing mice, Dox treatments (5mg/kg, 6 days) decreased the numbers of BMSCs and white blood cells; conversely, those treatments increased the numbers of BCSCs (CD24(-)/CD44(+)/ESA(+)) more than threefold in the same mice. Furthermore, therapeutic-dose of Dox (1mg/kg/week, 42 days) decreased the numbers of BMSCs while it increased BCSCs in vivo. Breast cancer cells, rather than bone marrow cells, highly expressed GCS, which was induced by Dox and correlated with BCSC pluripotency. These results indicate that Dox may have opposite effects, suppressing BMSCs versus expanding BCSCs, and GCS is one determinant of the differentiated responsiveness of bone marrow and cancer cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID: 22728310

 

Supplementary picture:

 

Yong-Yu Liu-2

The difference of glucosylceramide synthase (GCS) levels in bone marrow stem cells and breast cancer stem cells determines their responses to doxorubicin treatments. Doxorubicin causes cell death of bone marrow stem cells that have low levels of GCS and results in bone marrow suppression. Doxorubicin kills differentiated cancer cells, however, breast cancer stem cells that have high levels of GCS survive and proliferate. Increased breast cancer stem cells may lead tumor progression.

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