Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.
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This work was supported by the Leukemia and Lymphoma Society (CTJ, 6230-11), Department of Defense (CTJ, W81XWH-07-1-0601), NY State Stem Cell Foundation (CTJ, C024964), National Institutes of Health (AF, RO1 GM079364), (ADK, PO1 CA125066) and a Wilmot-Roswell Park Collaborative Seed Grant. KPC was supported by American Cancer Society (PF-10-054-01-LIB) and Wilmot Cancer Center postdoctoral fellowships.
The authors declare no conflict of interests.
KPC designed research, performed experiment, and wrote the paper; CTJ designed research and wrote the paper; MM, CC, EDL, RMR, MBB, LP, SJ, AF, MRG, ADK, JLL, MWB performed experiments and analyzed data.
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Callahan, K., Minhajuddin, M., Corbett, C. et al. Flavaglines target primitive leukemia cells and enhance anti-leukemia drug activity. Leukemia 28, 1960–1968 (2014). https://doi.org/10.1038/leu.2014.93