Evaluation of artemisinins for the treatment of acute myeloid leukemia

Christina D. Drenberg, Jassada Buaboonnam, Shelley J. Orwick, Shuiying Hu, Lie Li, Yiping Fan, Anang A. Shelat, R. Kiplin Guy, Jeffrey Rubnitz, Sharyn D. Baker

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)1231-1243
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume77
Issue number6
DOIs
StatePublished - Jun 1 2016

Bibliographical note

Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.

Keywords

  • Acute myeloid leukemia
  • Artemisinin
  • Chemotherapy
  • Cytarabine
  • High-throughput screen

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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