Department of Bioengineering, University of Washington, Seattle, WA, U.S.A.
Department of Chemistry, University of Washington, Seattle, WA, U.S.A.
Anticancer Res. 2014 Jun;34(6):2807-10.
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.
青蒿素与铁反应时会产生细胞毒性自由基。它的毒性对癌细胞更具选择性，因为癌细胞内含有更高水平的细胞内游离铁。我们之前曾报道过青蒿素的一种活性代谢物二氢青蒿素（DHA）对莫尔托-4 人淋巴母细胞具有选择性细胞毒性。一个担忧是，癌细胞在反复给药后是否会对 DHA 产生耐药性，从而限制其治疗效果。在本研究中，我们通过在体外将莫尔托-4 细胞暴露于逐渐增加的 DHA 浓度，开发了一种 DHA 耐药的莫尔托-4 细胞系（RTN）。RTN 细胞对 DHA 的半数最大抑制浓度（IC50）比莫尔托-4 细胞高 7.1 倍。RTN 细胞的生长速度比莫尔托-4 细胞快。此外，我们还研究了两种更有效的合成青蒿素化合物青蒿素二聚体-醇和青蒿素标记的转铁蛋白对 RTN 细胞的毒性；RTN 细胞对这些化合物没有明显的交叉耐药性。
