Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.
Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.
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DOI：
10.18632/oncotarget.5156
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发表时间：
2015-10-13
期刊：
影响因子：
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通讯作者：
Tafuri A
中科院分区：
文献类型：
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作者：
Iacovelli S;Ricciardi MR;Allegretti M;Mirabilii S;Licchetta R;Bergamo P;Rinaldo C;Zeuner A;Foà R;Milella M;McCubrey JA;Martelli AM;Tafuri A
在急性淋巴细胞白血病（ALL）中已经记录了几种化学抗性机制，包括Bcl-2蛋白家族过表达和PI 3 K/Akt/mTOR信号传导的组成性激活，鼓励靶向方法来规避该临床问题。在这里，我们分析了BH 3模拟物ABT-737在ALL中的活性，探索了与mTOR抑制剂CCI-779对ABT-737抗性细胞的协同作用。我们发现，低Mcl-1/Bcl-2加Bcl-xL蛋白比例决定ABT-737的反应性。ABT-737暴露进一步降低Mcl-1，诱导敏感模型和原始样品的细胞凋亡，而不影响耐药细胞。Bcl-2和mTOR通路的共抑制通过以不依赖于蛋白酶体的方式下调mTORC 1活性和Mcl-1而对ABT-737耐药模型产生细胞毒性。虽然Mcl-1似乎是至关重要的，异位调制并不与凋亡的变化。重要的是，双重靶向证明对ABT-737抗性样品有效，显示出累加/协同效应。总之，我们的结果显示了BH 3模拟物作为单一药剂在大多数ALL样品中的功效，并证明对ABT-737的抗性主要与Mcl-1过表达相关。共靶向Bcl-2蛋白家族和mTOR通路通过抑制Mcl-1增强了药物诱导的细胞毒性，为克服ALL中的BH 3模拟物耐药性提供了一种新的治疗方法。
Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL.