Abstract 4233A: The opposite effects of doxorubicin on bone marrow cells versus cancer cells in vivo depend on glucosylceramide synthase

Abstract

Abstract Bone marrow suppression and tumor drug resistance are adverse effects observed in patients with chemotherapy severely limit cancer treatments. It is unclear by which cellular mechanism anticancer drugs suppress bone marrow while drug-resistant tumor survives. We report that due to the difference in the glucosylceramide synthase (GCS) that catalyzes ceramide glycosylation determining ceramide-induced apoptosis or glycosphingolipid mediated maintenance of stem cells, doxorubicin can eliminate bone marrow stem cells and expand cancer stem cells. Doxorubicin treatments significantly decreased the number of bone marrow stem cells (BMSCs, ABCG2+) and sphere formation in dose-dependent fashion (1-5 mg/kg). In tumor-bearing mice, doxorubicin treatments (6 days) significantly decreased bone marrow stem cells and peripheral blood cells at 2 mg/kg and 5 mg/kg. In contrast, doxorubicin increased the number of breast cancer stem cells (BCSCs, CD24-/CD44+/ESA+) more than 3 times at 5 mg/kg treatment. Furthermore, silencing GCS with MBO-asGCS prevented BCSC number increase. Similarly, therapeutic-dose of doxorubicin (1 mg/kg/week, i.p., for 42-days), decreased bone marrow stem cells and increased breast cancer stem cells. Breast cancer cells, but not bone marrow cells, highly expressed glucosylceramide synthase (GCS) which was associated with pluripotency of stem cells. These results indicate that doxorubicin may have the opposite effects, suppressing BMSC versus expanding BCSC in vivo, and GCS is a determinant for the differentiated responsiveness between bone marrow cells, and breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4233A. doi:1538-7445.AM2012-4233A