DNA damage in dihydroartemisinin-resistant Molt-4 cells.
Artemisinin generates carbon-based free radicals when it reacts with iron, and induces molecular damage and apoptosis. Its toxicity is more selective toward cancer cells because cancer cells contain a higher level of intracellular free iron. Dihydroartemisinin (DHA), an analog of artemisinin, has selective cytotoxicity toward Molt-4 human lymphoblastoid cells. A major concern is whether cancer cells could develop resistance to DHA, thus limiting its therapeutic efficacy. We have developed a DHA-resistant Molt-4 cell line (RTN) and found out that these cells exhibited resistance to DHA but no significant cross- resistance to artemisinin-tagged holotransferrin (ART-TF), a synthetic artemisinin compound. In the present study, we investigated DNA damage induced by DHA and ART-TF in both Molt-4 and RTN cells using the comet assay. RTN cells exhibited a significantly lower level of basal and X-ray-induced DNA damage compared to Molt-4 cells. Both DHA and ART-TF induced DNA damage in Molt-4 cells, whereas DNA damage was induced in RTN cells by ART-TF, and not DHA. The result of this study shows that by the cell selection method, it is possible to generate a Molt-4 cell line which is not sensitive to DHA, but sensitive to ART-TF, as measured by DNA damage.
Department of Bioengineering, University of Washington, Seattle, WA, U.S.A.
Jungsoo
J
Park
Department of Bioengineering, University of Washington, Seattle, WA, U.S.A.
Henry C
HC
Lai
Department of Chemistry, University of Washington, Seattle, WA, U.S.A.
Tomikazu
T
Sasaki
Department of Bioengineering, University of Washington, Seattle, WA, U.S.A. narendra@uw.edu.
Narendra P
NP
Singh
D000970:Antineoplastic Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D014168:Transferrin / Q000494:pharmacology
D000970:Antineoplastic Agents; D037621:Artemisinins; D014168:Transferrin; C110714:holotransferrin; C039060:artenimol; C031327:artemisinin
DNA damage; Dihydroartemisinin; artemisinin-tagged holotransferrin; comet assay; dihydroartemisinin-resistant Molt-4 cells