Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells.
Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells.
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DOI：
10.18632/oncotarget.8742
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发表时间：
2017-03-07
期刊：
影响因子：
--
通讯作者：
Russell N
中科院分区：
文献类型：
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作者：
Pallis M;Burrows F;Ryan J;Grundy M;Seedhouse C;Abdul-Aziz A;Montero J;Letai A;Russell N
增敏剂分子BAD和NOXA在介导细胞凋亡方面的直接合作表明，对BAD敏感的治疗剂可能是对NOXA敏感剂的补充。动态BH3图谱是一种新的方法学，我们已将其应用于测量增敏剂BH3多肽模拟物和治疗药物之间的互补性。用动态BH3图谱显示，在急性髓系白血病(AML)细胞中，下调MCL-1的药物TG02对bcl2抑制的Bad-BH3多肽敏感，而bcl2拮抗剂ABT-199对MCL-1抑制的noxa-BH3多肽敏感。在所使用的浓度下，这些多肽本身并不会触发线粒体外膜的通透性，但会在适当触发互补途径的情况下启动细胞释放细胞色素C。在KG-1a细胞中，TG02和ABT-199协同诱导细胞凋亡。在不同种类的AML患者样本中，我们注意到对这两种药物的一系列敏感性。尽管一些单独的样本明显偏爱一种或另一种药物，但在整个小组中，TG02+ABT-199的组合比单独使用任何一种药物的细胞毒性要大得多。我们得出结论，动态NOXA和BAD BH3图谱是研究药物作用的分子途径和化学反应的互补机制的一种敏感的方法。
Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells. At the concentrations used, the peptides did not trigger mitochondrial outer membrane permeabilisation in their own right, but primed cells to release Cytochrome C in the presence of an appropriate trigger of a complementary pathway. In KG-1a cells TG02 and ABT-199 synergised to induce apoptosis. In heterogeneous AML patient samples we noted a range of sensitivities to the two agents. Although some individual samples markedly favoured one agent or the other, in the group as a whole the combination of TG02 + ABT-199 was significantly more cytotoxic than either agent individually. We conclude that dynamic NOXA and BAD BH3 profiling is a sensitive methodology for investigating molecular pathways of drug action and complementary mechanisms of chemoresponsiveness.