INHIBITION OF MITOCHONDRIAL TRANSLATION AS A THERAPEUTIC STRATEGY FOR HUMAN ACUTE MYELOID LEUKEMIA
By M. Škrtić, S. Sriskanthadevan, Bozhena Jhas, Marinella Gebbia, Xiaoming Wang, Zezhou Wang, R. Hurren, Y. Jitkova, M. Gronda, N. MacLean and 19 more. Cancer Cell, 2011
635 citations recorded by the source corpus.
SUMMARY 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 anti-leukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the anti-leukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis which, 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.
Subfields: Hematology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/171b42a5621702fce120d01b599351ca7af5a68f
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Citations in the corpus
- High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. (2015, neutral): “Several antibacterial drugs, including linezolid (Nagiec et al., 2005), tigecycline (Olson et al., 2006), and chloramphenicol (McKee et al., 2006), have been shown to specifically inhibit mitochondrial ribosome function in mammalian cells (Figure 5H) (Skrti c et al., 2011).”
- A census of human RNA-binding proteins (2014, background): “inhibiting the translation initiation factors EIF4A1 and 2 (Grzmil and Hemmings, 2012; Hein et al., 2013; Silvera et al., 2010; Skrtić et al., 2011).”
- ROS homeostasis and metabolism: a dangerous liason in cancer cells (2016, methodology): “been designed and currently successfully employed in preclinical studies.(77,159) Although the potential utility of these compounds still needs to be validated in long-term clinical trials, encouraging evidences suggest that targeting the bioenergetics function of the mitochondria might represent a ”