褪黑素促进MCL-1抑制剂诱导白血病细胞凋亡的分子机制研究

BCL-2家族蛋白在白血病发生发展及耐药过程中起重要作用。MCL-1抑制剂是一类新型靶向药物，但是在临床试验上仍然存在毒副作用和耐药性等问题。我们前期发现，常用睡眠辅助药物褪黑素能显著增强MCL-1抑制剂对多种白血病细胞的杀伤效果，并极大降低药物的使用剂量。在多个血液瘤细胞系中发现，褪黑素能够特异性地激活死亡受体途径关键信号因子Caspase-8。此外，在Jurkat bak敲除细胞系中结果显示，褪黑素与药物诱导的细胞凋亡依赖于BAK/BAX。因此，我们推测褪黑素诱导的死亡受体途径凋亡可能是通过Caspase-8-BID-BAK/BAX通路来起作用的。本项目拟在前期研究基础上，利用生理生化、分子和动物模型等手段探讨褪黑素和MCL-1抑制剂联用诱导血液瘤细胞发生凋亡的分子机制。本研究不仅有助于揭示褪黑素和药物联用诱导细胞凋亡新的作用机制，也为褪黑素应用于临床治疗白血病奠定基础。

BCL-2 family members are closely related to the initiation and development of the malignant tumors, and as well as chemo-drug resistance. The MCL-1 inhibitors were recently developed as target chemo drugs for the treatment of many malignancies. Most of them are still under clinical trials, but already showed some severe side effects. Our previous results showed that, melatonin, which was currently used as sleep medicine, can promote the cell apoptosis induced by MCL-1 inhibitors with significantly reduced drug dosages. Importantly, our results showed that melatonin could activate the cell death signaling pathway by increasing the level of cleaved Caspase-8, indicating possible novel mechanisms of melatonin in the regulation of cell apoptosis in leukemia cells. Our previous results further showed that although melatonin and MCL-1 inhibitor could activate the cell death signaling pathway and induce the cell apoptosis, but the effect was still dependent on the BAK/BAX, indicating that melatonin and MCL-1 could coordinately induce the cell apoptosis via the Caspase-8-BID-BAK/BAX cascade. Thus, based on our previous results, this study aims to further investigate the molecular mechanism of melatonin and MCL-1 inhibitor in the regulation of cell apoptosis in leukemia cells, by using molecular, biochemical, cellular and animal experiments. This study will not only reveal the novel mechanisms of melatonin and MCL-1 inhibitor in the regulation of cell apoptosis in leukemia, but also provides evidences for melatonin being used as a promising adjuvant drug for the clinical leukemia trials.