髓系白血病
癌症研究
细胞凋亡
白血病
U937电池
细胞培养
髓样
程序性细胞死亡
医学
下调和上调
体内
药理学
生物
免疫学
基因
生物化学
遗传学
生物技术
作者
Qiang Liu,Kenichiro Doi,Krishne Gowda,Brian M. Barth,David F. Claxton,Shantu Amin,Thomas P. Loughran,Honggang Wang
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2014-10-01
卷期号:74 (19_Supplement): 1807-1807
标识
DOI:10.1158/1538-7445.am2014-1807
摘要
Abstract There is an urgent and unmet medical need for development of new therapeutics for acute myeloid leukemia (AML). The anti-apoptotic Bcl-2 family protein Mcl-1 plays a critical role in AML cell survival and chemoresistance. Mcl-1 is upregulated in relapsed AML and leukemic stem cells. Inhibition of Mcl-1 expression in AML cells by kinase inhibitors or gene targeting induces apoptosis and suppresses leukemogenesis. However, the impact of targeting Mcl-1 in AML therapy with selective pharmacological inhibitors remains to be assessed. Recently, we discovered a novel Mcl-1 inhibitor, maritoclax (marinopyrrole A), which antagonizes Mcl-1 by targeting Mcl-1 for proteasomal degradation. This unique mechanism of action is in contrast to BH3 mimetics that exert their inhibitory function through disruption of the interactions between pro- and anti-apoptotic Bcl-2 family proteins. In a panel of AML cell lines, the potency of maritoclax positively correlated with Mcl-1 expression and inversely correlated with Bcl-2 and Bcl-xL expression. Maritoclax was efficacious as a single agent and markedly synergized with ABT-737 to induce apoptosis in Mcl-1 overexpressing ABT-737 and multidrug resistant AML cell lines. Moreover, maritoclax was able to overcome stroma-mediated resistance to apoptosis in AML cells. Importantly, maritoclax induced Mcl-1 degradation and apoptotic cell death selectively in clinical AML specimens with high levels of Mcl-1. To evaluate the anti-tumor activity of maritoclax in vivo, we established U937 tumor xenografts in nude mice. As a single agent, maritoclax significantly inhibited the growth of established xenografts at a dose of 20 mg/kg/d intraperitoneally. At this dosing level, no significant difference in body weight change and complete blood count was observed between maritoclax and vehicle treatment groups. Collectively, our studies demonstrated that maritoclax represents a novel class of Mcl-1 inhibitors and that the selective pharmacological inhibition of Mcl-1 may be a viable approach for the treatment of AML. Citation Format: Qiang Liu, Kenichiro Doi, Krishne Gowda, Brian M. Barth, David Claxton, Shantu Amin, Thomas P. Loughran, Hong-Gang Wang. Pre-clinical evaluation of Mcl-1 inhibition through maritoclax in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1807. doi:10.1158/1538-7445.AM2014-1807
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