title: Development of a dihydroartemisinin-resistant Molt-4 leukemia cell line.
abstract: Artemisinin generates cytotoxic free radicals when it reacts with iron. Its toxicity is more selective toward cancer cells because cancer cells contain a higher level of intracellular-free iron. We previously reported that dihydroartemisinin (DHA), an active metabolite of artemisinin, has selective cytotoxicity toward Molt-4 human lymphoblastoid cells. A concern is whether cancer cells could develop resistance to DHA after repeated administration, thus limiting its therapeutic efficacy. In the present study, we developed a DHA-resistant Molt-4 cell line (RTN) by exposing Molt-4 cells to gradually increasing concentrations of DHA in vitro. The half-maximal inhibitory concentration (IC50) of DHA for RTN cells is 7.1-times higher than that of Molt-4 cells. RTN cells have a higher growth rate than Molt-4 cells. In addition, we investigated the toxicities of two more potent synthetic artemisinin compounds, artemisinin dimer-alcohol and artemisinin-tagged holotransferrin toward RTN cells; RTN cells showed no significant cross-resistance to these compounds.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA, U.S.A.
authors.forename: Jungsoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA, U.S.A.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Lai
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA, U.S.A.
authors.forename: Mallika
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA, U.S.A.
authors.forename: Tomikazu
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA, U.S.A. narendra@uw.edu.
authors.forename: Narendra P
authors.initials: NP
authors.lastname: Singh
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D014168:Transferrin / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D014168:Transferrin; C110714:holotransferrin; C039060:artenimol; C031327:artemisinin
keywords: Dihydroartemisinin; artemisinin dimer; artemisinin-tagged holotransferrin; dihydroartemisinin-resistant Molt-4 cells