The Effect Of Emodin Derivative On Proliferation Inhibition And Apoptosis Induction In Chronic Myelogenous Leukemia Cell K562and Imatinib-resistant K562/G01

[Objective] On the basis of emodin, we designed and synthesized10kinds ofderivatives. Among them, we select the most effective on inhibition of proliferation inleukemia cells. The selected emdoin derivative was used to explore the effect onproliferation inhibition and apoptosis induction in human chronic myeloid leukaemia(CML) cell line K562, IM-resistant CML cell line K562/G01.And its mechanismswere also explored..[Methods] MTT assay were used to access the cell proliferation. The following celllines were included: K562cell, IM-resistant CML cell line K562/G01and ADM-resistant cell line KAR. Colony formation assay was another measurement of cellproliferation. Apoptotic induction effects were examined by DAPI staining methodand DNA ladder assay. The effects of E19on the protein expressions were tested byWestern blot, including Bcl-2、c-Myc、procaspase-9、cleaved Caspase-3and PARP.Western blot was also performed to detect the changes of some crucial molecules inP210Bcr-Abl、PI3K/Akt/mTOR and MAPK signaling pathways.[Results](1)10kinds of emodin derivatives were synthesized, and the bioactivity ofderivatives differed from each other. Among them, the bioactivity of derivative E19was the best.(2)E19inhibited K562cells proliferation with an average IC50valueof1.1966±0.1949μmol/L, the K562/G01cells’ IC50was1.2157±0.1642μmol/L.E19inhibited growth in K562and K562/G01cells in time-dependent anddose-dependent manners.(3)E19could also suppress K562and K562/G01cells clone formation significantly, in dose-dependent manner.(4)From DAPI staining methodand DNA ladder assay, we observed E19induced cell apoptosis in K562andK562/G01cells in a dose-dependent way.(5)In K562and K562/G01cells, theexpressions of Bcl-2、c-Myc、procaspase-9、PARP were down-regulated. E19up-regulated cleaved Caspase-3, which lead to the induction of apoptosis. E19inhibited phosphorylation of P210Bcr-Abl, Akt, mTOR,4EBP1, p70, MAPK of P210,PI3K/Akt/mTOR and MAPK signaling pathways. The inhibitory effects were shownin a time-dependent and dose-dependent manners.[Conclusion] Among10kinds of Emodin derivatives, E19could efficiently inhibitproliferation and induce apoptosis in K562and K562/G01cells. Inhibition in P210,PI3K/Akt/mTOR and MAPK signaling pathways may play critical roles in themechanisms of proliferation inhibition and apoptosis induction.