The opposite effects of doxorubicin on bone marrow stem cells versus breast cancer stem cells depend on glucosylceramide synthase.
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.
Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, LA 71209, USA.
Kaustubh N
KN
Bhinge
Vineet
V
Gupta
Salman B
SB
Hosain
Seetharama D
SD
Satyanarayanajois
Sharon A
SA
Meyer
Benny
B
Blaylock
Qian-Jin
QJ
Zhang
Yong-Yu
YY
Liu
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D001943:Breast Neoplasms / Q000097:blood / Q000201:enzymology / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D005964:Glucosyltransferases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D017239:Paclitaxel / Q000633:toxicity; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D004317:Doxorubicin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D017239:Paclitaxel