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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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NEOPLASIA
An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells
Monica L. Guzman1,
Randall M. Rossi1,
Sundar Neelakantan2,
Xiaojie Li1,
Cheryl A. Corbett1,
Duane C. Hassane1,
Michael W. Becker1,
John M. Bennett1,
Edmund Sullivan3,
Joshua L. Lachowicz4,
Andrew Vaughan5,
Christopher J. Sweeney6,
William Matthews7,
Martin Carroll8,
Jane L. Liesveld1,
Peter A. Crooks2, and
Craig T. Jordan1
1 James P. Wilmot Cancer Center, University of Rochester, NY;
2 College of Pharmacy, University of Kentucky, Lexington;
3 Advanced Veterinary Services, Bellingham, WA;
4 Redbank Veterinary Hospital, Tinton Falls, NJ;
5 Las Vegas Veterinary Referral Center, NV;
6 Department of Medicine, Indiana University School of Medicine, Indianapolis;
7 Leuchemix, Woodside, CA; and
8 Division of Hematology and Oncology, University of Pennsylvania, Philadelphia
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 pharmacologic 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 LSCs 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- B, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic 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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