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Cancer Stem Cells
Article first published online: 19 DEC 2012
Copyright © 2012 AlphaMed Press
Volume 31, Issue 1, pages 23–34, January 2013
How to Cite
Yuan, S., Wang, F., Chen, G., Zhang, H., Feng, L., Wang, L., Colman, H., Keating, M. J., Li, X., Xu, R.-H., Wang, J. and Huang, P. (2013), Effective Elimination of Cancer Stem Cells By a Novel Drug Combination Strategy. STEM CELLS, 31: 23–34. doi: 10.1002/stem.1273
Author contributions: S.Y. and F.W.: conception and design, collection/assembly of data, data analysis/interpretation, manuscript writing, and final approval; G.C., H.Z., L.W., H.C., M.K., R.X., and J.W.: provision of study materials and final approval; L.F.: collection/assembly of data; X.L.: design of animal study and data analysis/interpretation; P.H.: conception and design, provision of study materials, data analysis/interpretation, and final approval; S.Y. and F.W. contributed equally to this article.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS November 6, 2012.
- Issue published online: 19 DEC 2012
- Article first published online: 19 DEC 2012
- Accepted manuscript online: 6 NOV 2012 11:33PM EST
- Manuscript Accepted: 29 SEP 2012
- Manuscript Received: 1 MAY 2012
- major science and technology project
- National Basic Research Program (973 Program) of China. Grant Numbers: 2012CB967004, CA085563, CA100428, CA16672
- National Institutes of Health
- CLL Global Research Foundation
- Rosalie B Hite Fellowship from MD Anderson Cancer Center
- Drug target;
Development of effective therapeutic strategies to eliminate cancer stem cells, which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide (TMZ), but showed high sensitivity to a glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), especially under hypoxic conditions. We further showed that combination of 3-BrOP with carmustine but not with TMZ achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine-induced DNA repair. This drug combination significantly impaired the sphere-forming ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3-BrOP and carmustine inhibited glyceraldehyde-3-phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties. STEM Cells2013;31:23–34