title: Evaluation of artemisinins for the treatment of acute myeloid leukemia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 W. 12th St., Columbus, OH, 43210, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Christina D
authors.initials: CD
authors.lastname: Drenberg
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jassada
authors.initials: J
authors.lastname: Buaboonnam
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Orwick
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 W. 12th St., Columbus, OH, 43210, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rubnitz
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 W. 12th St., Columbus, OH, 43210, USA. baker.2480@osu.edu.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. baker.2480@osu.edu.
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077332:Artesunate; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D057166:High-Throughput Screening Assays; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000473:pathology; D008815:Mice, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D037621:Artemisinins; D017382:Reactive Oxygen Species; D003561:Cytarabine; D000077332:Artesunate; C039060:artenimol
keywords: Acute myeloid leukemia; Artemisinin; Chemotherapy; Cytarabine; High-throughput screen