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Ouabain has shown powerful anti-proliferation activities in various cancers, but its effect on imatinib)resistant chronic myeloid leukemia and toxicity on normal mice has not been investigated. Cell Counting Kit-8 assay was used to detect cytotoxicity and reversal effect of ouabain with different concentration (0.01 µM, 0.1 µM, 1.0 µM, 10 µM) on drug resistance of imatinib-resistant cell line of chronic myeloid leukemia (K562/G01 cell line). Flow cytometry was used to detect the apoptosis effect and cell cycle arrest. Hematological examination, biochemical examination and histological examination were used to detect sub-chronic toxicity of ouabain on healthy mice. In our present study, ouabain showed greatly inhibitory effect and significantly reduced half minimal inhibitory concentration of imatinib in K562/ G01 cells, an imatinib-resistant cell line of chronic myeloid leukemia, in a dose- and time- dependent manner, which implied that ouabain increased cell sensitivity to imatinib. Ouabain enhanced apoptosis induced by imatinib in K562/G01 cells not through cell cycle arrest. Animal experiments showed that there were no significant variances in hematological, liver function, kidney function parameters and organ histopathology of all mice groups. These data suggested that ouabain could be a potential agent to treat imatinib-resistant chronic myeloid leukemia for its powerful cytotoxicity as well as reversal effect, but further study is needed to find out its specific mechanism. [ABSTRACT FROM AUTHOR]