【摘 要】
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BACKGROUND: Increasing evidence indicates that the plasma membrane contains an essential electron transport system that is used particularly by highly glycolytic cancers to oxidize intracellular NADH
【机 构】
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Department of Radiation Therapy University of Otago Wellington New Zealand
【出 处】
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BIT‘s2nd Annual World Cancer Congess-2009 (2009第二届癌症大会)
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BACKGROUND: Increasing evidence indicates that the plasma membrane contains an essential electron transport system that is used particularly by highly glycolytic cancers to oxidize intracellular NADH in support of continued glycolytic ATP production.This suggests that plasma membrane electron transport (PMET) may be a primary site of action for the anticancer activity ofredox-active lipophilic flavonoids such as phenoxodiol.We previously showed that phenoxodiol inhibits PMET and induces apoptosis in a range of cancer cell lines but not in non-transformed WI-38 cells and HUVECs.METHODS: We determined the effects of phenoxodiol on PMET, proliferation and viability of activated and resting human T cells.In addition, we evaluate the effect ofphenoxodiol on the viability of leukemic cell lines and primary leukemic blasts isolated from patient bone marrows.RESULTS: We demonstrated that phenoxodiol inhibits PMET and cell proliferation and promotes apoptosis of rapidly proliferating human T cells but does not affect resting T cells.Phenoxodiol also induced apoptosis in T cells stimulated in HLA-mismatched allogeneic mixed lymphocyte reactions (MLR).Conversely, non-proliferating T cells in the MLR remained viable and could be successfully restimulated in a third party MLR, in the absence of phenoxodiol.In addition, we demonstrated that leukemic cell lines and leukemic blasts from the bone marrow of AML (n=22) and ALL (n=8) patients were variably sensitive to phenoxodiol, with ALL blasts being more sensitive than AML blasts (23 ± 4% and 64 ± 5% respectively, p=0.0002).CONCLUSION: The ability ofphenoxodiol to kill rapidly proliferating T cells makes this drug a promising candidate for the treatment of inappropriately or pathologically activated lymphocytes leukemias, lymphomas, auto-immune diseases and graft versus host disease.
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