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Arsenic trioxide inhibits P-glycoprotein expression in multidrug-resistant human leukemia K562/ADM cell line that overexpresses mdr-1 gene and enhances their chemotherapeutic sensitivity

WEI Hu-lai *, YAO Xiao-jian, LI Yu-ning, WANG Pei, ZHAO Huai-shun, BAI De-cheng, PENG Xiao, MA Lan-fang. Laboratory Center for Medical Science, Lanzhou Medical College, Lanzhou 730000, China  
Objective To investigate the effects of arsenic trioxide (As 2O 3) on the apoptosis and P-glyco-protein (P-gp) expression of multidrug-resistant human leukemia K562/ADM cells, and the combined effects of As 2O 3 with conventional chemotherapeutic agents. Methods Multidrug-resistant human leukemia cell line K562/ADM that overexpresses mdr-1 gene was used as the target cells. The cell proliferating activity was assessed with a MTT assay. Cell morphology was examined by light microscopy, confocal microscopy and electron-microscopy. P-gp expression, cell-cycle status were determined by flow cytometry. Results K562/ADM cells were highly resistant to adriamycin, and cross-resistant to daunorubicin and etoposide. As 2O 3 at concentrations of 0.5 to 20 μmol/L inhibited the proliferation of K562/ADM cells, and K562/ADM cells were more sensitive to As 2O 3 than their parent K562 cells did. As 2O 3 induced marked apoptosis of K562/ADM cells showed by typical apoptotic morphological changes and the appearance of high sub-G 1 cell population. As 2O 3 significantly inhibited the P-gp expression in K562/ADM cells, and exerted a synergistic effect on the enhancement of the cell sensitivity to adriamycin, daunorubicin and etoposide. Conclusion As 2O 3 induces growth-inhibition and apoptosis of multidrug-resistant K562/ADM cells, and augments synergistically the sensitivity of the cells to conventional chemotherapeutic agents via down-regulation of P-gp expression.
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