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Evaluation of artemisinins for the treatment of acute myeloid leukemia

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Abstract

Purpose

Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models.

Methods

Using ten human AML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models.

Results

ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo.

Conclusions

The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML.

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Acknowledgments

This study was supported by the American Lebanese Syrian Associated Charities (ALSAC), National Institutes of Health Cancer Center Support Grant P30 CA021765, R01 CA138744 (SDB), and F32 CA180513 (CDD).

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Authors and Affiliations

  1. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 W. 12th St., Columbus, OH, 43210, USA

    Christina D. Drenberg, Shuiying Hu & Sharyn D. Baker

  2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA

    Christina D. Drenberg, Shelley J. Orwick, Shuiying Hu & Sharyn D. Baker

  3. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jassada Buaboonnam & Lie Li

  4. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Yiping Fan

  5. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Anang A. Shelat & R. Kiplin Guy

  6. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jeffrey Rubnitz

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  1. Christina D. Drenberg
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  2. Jassada Buaboonnam
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Correspondence to Sharyn D. Baker.

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Drenberg, C.D., Buaboonnam, J., Orwick, S.J. et al. Evaluation of artemisinins for the treatment of acute myeloid leukemia. Cancer Chemother Pharmacol 77, 1231–1243 (2016). https://doi.org/10.1007/s00280-016-3038-2

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  • DOI: https://doi.org/10.1007/s00280-016-3038-2

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