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Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy.
Cancer Cell ( IF 50.3 ) Pub Date : 2017-Dec-11 , DOI: 10.1016/j.ccell.2017.11.003
Rongqing Pan , Vivian Ruvolo , Hong Mu , Joel D. Leverson , Gwen Nichols , John C. Reed , Marina Konopleva , Michael Andreeff

Evasion of apoptosis is a hallmark of cancer. Bcl-2 and p53 represent two important nodes in apoptosis signaling pathways. We find that concomitant p53 activation and Bcl-2 inhibition overcome apoptosis resistance and markedly prolong survival in three mouse models of resistant acute myeloid leukemia (AML). Mechanistically, p53 activation negatively regulates the Ras/Raf/MEK/ERK pathway and activates GSK3 to modulate Mcl-1 phosphorylation and promote its degradation, thus overcoming AML resistance to Bcl-2 inhibition. Moreover, Bcl-2 inhibition reciprocally overcomes apoptosis resistance to p53 activation by switching cellular response from G1 arrest to apoptosis. The efficacy, together with the mechanistic findings, reveals the potential of simultaneously targeting these two apoptosis regulators and provides a rational basis for clinical testing of this therapeutic approach.

中文翻译:

联合Bcl-2抑制和p53激活在AML中的合成杀伤力:机制和优异的抗白血病功效。

规避细胞凋亡是癌症的标志。Bcl-2和p53代表凋亡信号通路中的两个重要节点。我们发现伴随的p53激活和Bcl-2抑制克服了细胞凋亡抗性,并在耐药性急性髓性白血病(AML)的三种小鼠模型中显着延长了生存期。从机制上讲,p53激活负调控Ras / Raf / MEK / ERK途径并激活GSK3以调节Mcl-1磷酸化并促进其降解,从而克服了AML对Bcl-2抑制的抗性。此外,Bcl-2抑制通过切换G 1的细胞应答而克服了对p53激活的凋亡抗性。阻止凋亡。该功效以及机理发现揭示了同时靶向这两种凋亡调节剂的潜力,并为该治疗方法的临床测试提供了合理的基础。
更新日期:2017-12-11
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