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- W1544481176 abstract "4709 4-(4-bromopheny1)-2,3-dihydro-N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmidazole-1-carboxamide (MZ3), one of 2-oxo-N,3,4-trisubstituted-penylimidazoline-1-carboxamides modified from Combretastatin A-4 (a potent agent of Combretum Caffrum ), displayed a specific activity against leukemia cell lines. A panel of six human leukemia cells (HL60, K562, Molt-4 and NB4, 2 multi-drug resistant cell lines: HL60R, K562R) were employed to determine the cytotoxicity through MTT assay and flow cytometry. MZ3 exhibited high anti-leukemia activity in all cell lines with IC 50 values ranged from 1.2 μM to 8.0 μM. MZ3 (4.0 μM for 6 - 72 h) induced apoptosis in 2.5 % - 85.4 % of HL60 cells in a time-dependent manner. By fluorescence stain assay, an elevation of reactive oxygen species (ROS) level was observed in HL60 cells treated with 8.0 μM MZ3 at 2 hours, preceding an occurrence of mitochondrial membrane potential (ΔΨ m ) loss at 8 h, indicating that MZ3 activated the mitochondrial pathway of apoptosis via ROS. The loss of ΔΨ m was reported as a pro-apoptotic factor that could induce the activation of caspase cascade, therefore we tested the expression of proteins related to apoptosis by western blot. The results showed that MZ3 induced the activation of procaspase-3 and subsequent cleavage of its substrate poly (ADP-ribose) polymerase (PARP), while decreased the expression of the x-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic protein. Since it was reported that the stabilization of mitochondrial membrane is regulated by the Bcl-2 family proteins and the ratio of Bax to Bcl-2 within a cell is critical for the cellular response to apoptotic stimuli, we determined protein expression of Bax and Bcl-2, and found a >4-fold increase of Bax/Bcl-2 ratio in HL60 cells treated with 8.0 μM MZ3 for 24 h. To supplement our results, the activity assay in vivo was performed on severe combined immunodeficiency (SCID) mice model of human leukemia engraftment. The median survival time (MST) in treatment group, administrated (i.m.) with 10 mg/kg MZ3 daily for 10 consecutive days, was significantly prolonged ( P in vitro and in vivo , and mitochondrial pathway might be involved in the activation of a caspase cascade to induce cell apoptosis." @default.
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- W1544481176 date "2006-04-15" @default.
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- W1544481176 title "4-(4-bromopheny1)-2,3-dihydro-N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmidazole-1-carboxamide induces apoptosis in human leukemia cells through mitochondrial pathway" @default.
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