Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia

TitleInhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia
Publication TypeJournal Article
Year of Publication2011
AuthorsSkrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, Hurren R, Jitkova Y, Gronda M, MacLean N, Lai CK, Eberhard Y, Bartoszko J, Spagnuolo P, Rutledge AC, Datti A, Ketela T, Moffat J, Robinson BH, Cameron JH, Wrana J, Eaves CJ, Minden MD, C Y Wang J, Dick JE, Humphries K, Nislow C, Giaever G, Schimmer AD
JournalCancer Cell
Volume20
Issue5
Pagination674-88
Date Published11/2011
ISSN1878-3686
Abstract

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.

DOI10.1016/j.ccr.2011.10.015
Alternate JournalCancer Cell
PubMed ID22094260
PubMed Central IDPMC3221282
Grant ListNCI 1R01CA157456 / CA / NCI NIH HHS / United States
R01 CA157456 / CA / NCI NIH HHS / United States
R01 CA157456-01 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada