科研之友
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摘要
We have synthesized a novel molecule named XB05 (1-bromo-1,1-difluoro-non-2-yn-4-ol) and evaluated its effects in a variety of human cell lines. XB05 displayed potent antiproliferative activity against cell lines derived from leukemia or solid tumors, but had less effect on nonmalignant cells. To identify factors that contribute to the cancer selectivity of XB05, we chose three cell lines that had high sensitivity to XB05 (U937 leukemia), moderate sensitivity (A549 lung cancer), or low sensitivity (Hs27 nonmalignant skin fibroblasts), and proceeded to assess cell death and oxidative stress in these cells. XB05 was found to induce cell death via both apoptotic and nonapoptotic mechanisms in U937 and A549 cells, whereas it had no cytotoxicity against Hs27 cells at comparable concentrations. Treatment with XB05 caused an increase in reactive oxygen species in all cell lines tested, but levels were higher in malignant compared to nonmalignant cells. XBO5 treatment also induced DNA damage exclusively in the malignant cells. Differences in antioxidant responses were observed between cell lines. For example, XBO5 caused a decrease in levels of glutathione and nuclear Nrf2 in the most sensitive cells (U937), whereas the least sensitive cells (Hs27) displayed increased glutathione levels and no change in nuclear Nrf2. XB05 could react in vitro with cysteine and glutathione, but had much lower reactivity compared to typical thiolreactive electrophiles, diethyl maleate and maleimide. In summary, XB05 is a novel compound that selectively kills malignant cells, most likely by disrupting cellular redox homeostasis, making it a promising candidate for development as a chemotherapeutic agent.
- 出版日期2014-3
