| Literature DB >> 24161946 |
Kimberly A Hartwell1,2,3, Peter G Miller2,3, Siddhartha Mukherjee4, Alissa R Kahn5, Alison L Stewart1, David J Logan1, Joseph M Negri1, Mildred Duvet1,4, Marcus Järås2, Rishi Puram2,3, Vlado Dancik1, Fatima Al-Shahrour1,2, Thomas Kindler2, Zuzana Tothova2,3, Shrikanta Chattopadhyay1,6, Thomas Hasaka1, Rajiv Narayan1, Mingji Dai1,7, Christina Huang1, Sebastian Shterental2, Lisa P Chu2, J Erika Haydu2, Jae Hung Shieh5, David P Steensma3,8, Benito Munoz1, Joshua A Bittker1, Alykhan F Shamji1, Paul A Clemons1, Nicola J Tolliday1, Anne E Carpenter1, D Gary Gilliland1,2,8,9, Andrew M Stern1, Malcolm A S Moore10, David T Scadden1,4,6, Stuart L Schreiber1,9,7, Benjamin L Ebert1,2,3,8, Todd R Golub1,3,9,11.
Abstract
Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.Entities:
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Year: 2013 PMID： 24161946 PMCID： PMC4009363 DOI： 10.1038/nchembio.1367
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040