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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4427-4435.
Prepublished online as a Blood First Edition Paper on September 5, 2007; DOI 10.1182/blood-2007-05-090621.
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Submitted May 15, 2007
Accepted August 25, 2007
An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells
Monica L Guzman, Randall M Rossi, Sundar Neelakantan, Xiaojie Li, Cheryl A. Corbett, Duane C Hassane, Michael W Becker, John M. Bennett, Edmund Sullivan, Joshua L. Lachowicz, Andrew Vaughan, Christopher J. Sweeney, William Matthews, Martin Carroll, Jane L. Liesveld, Peter A. Crooks, and Craig T. Jordan*
James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, United States
College of Pharmacy, University of Kentucky, Lexington, KY, United States
Bellingham Veterinary Care, Advanced Veterinarary Services, Bellingham, WA, United States
Department of Oncology, Redbank Veterinary Hospital, Tinton Falls, NJ, United States
Las Vegas Veterinary Referral Center, Las Vegas, NV, United States
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
Leuchemix, Inc., Woodside, CA, United States
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, United States
* Corresponding author; email: craig_jordan{at}urmc.rochester.edu.
Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally-occurring compound parthenolide (PTL) can induce death of human LSCs in vitro, while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacological properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylamino-parthenolide (DMAPT), which induces rapid death of primary human LSC from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-kB, and activation of p53. The compound has approximately 70% oral bioavailability and pharmacological studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo.
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