Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 44, Issue 11, Pages 1770-1778Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2012.06.010
Keywords
Myelosuppression; Doxorubicin; Glucosylceramide synthase; Breast cancer stem cells; Bone marrow
Categories
Funding
- National Center for Research Resources [5P20RR016456-11]
- National Institute of General Medical Sciences [8 P20 GM103424-11]
- National Institutes of Health
- Mizutani Foundation for Glycoscience
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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 (5 mg/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 (1 mg/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. (C) 2012 Elsevier Ltd. All rights reserved.
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