Synergistic Depression Of Wnt/β-catenin Pathway By Sequential Combination Of Decitabine And Idarubicin In Human Myeloid Leukemic Cell Lines

PART1. The Effect of Anti-leukemia Drugs in Combination with Decitabine of Inhibiting Growth in Myeloid Leukemic Cell Line Background and ObjectivesSelecting the most effective anti-leukemia drug in combination with DAC, as well as finding the most appropriate combination way.MethodsMyeloid leukemia cells (U937, HEL and SKM-1) were treated with decitabine alone, anti-leukemia drugs (idarubicin, daunorubicin aclarubicin, thalidomide, homoharringtonine) alone, and decitabine simultaneously or sequentially combination with anti-leukemia drugs to determine their impact on cellular proliferation by MTT method. ResultsDecitabine sequentially combined with idarubicin has synergistic effect in inhibiting proliferation of myeloid leukemic cell lines. PART2. Synergistic Depression of Wnt/β-catenin pathway by Sequential Combination of Decitabine and Idarubicin in Human Myeloid Leukemic Cell LinesBackground and ObjectivesIn the preliminary experiment, we investigated the effect of anti-leukemia drugs (idarubicin, daunorubicin, aclarubicin, thalidomide, homoharringtonine) in combination with decitabine of inhibiting growth of myeloid leukemic cell lines. The result showed relatively notable synergistic effect of sequential combination of decitabine and idarubicin. In searching the associated mechanism, we assessed the effect of sequential combination of decitabine and idarubicin in cell apoptosis and the regulation of wnt pathway.MethodsMyeloid leukemia cells (U937, HEL and SKM-1) were treated with decitabine alone, idarubicin alone, and decitabine sequential with idarubicin to determine their impact on cell apoptosis and the regulation of wnt pathway by detecting DNA methylation status, mRNA level and protein expression.ResultsThe sequential combination of decitabine and idarubicin produced synergistic inhibition of myeloid leukemia cells growth by apoptosis. Sequential treatment with both agents induced synergistic effect in re-expression or up-expression of wnt inhibitor genes (SFRP1, HDPR1and DKK3). Furthermore, we found that the down-steam genes of wnt pathway including β-catenin, c-myc and CyclinDl were down-regulated.ConclusionTaken together, these findings showed that decitabine sequentially combined with idarubicin has synergistic anti-leukemia effect, which suggest clinical potential in the treatment of myeloid leukemias.