Journal
CANCER CELL
Volume 20, Issue 5, Pages 674-688Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2011.10.015
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Funding
- Canadian Stem Cell Network
- Canadian Institutes for Health Research
- Leukemia and Lymphoma Society
- National Institutes of Health [NCI 1R01CA157456]
- Terry Fox Foundation
- MaRS Innovation
- Ontario Institute of Cancer Research
- Ontario Ministry of Research and Innovation
- Princess Margaret Hospital Foundation
- Ministry of Long Term Health and Planning in the Province of Ontario
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To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity.
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