The Bcl-2 Homology Domain 3 Mimetic ABT-737 Targets the Apoptotic Machinery in Acute Lymphoblastic Leukemia Resulting in Synergistic in Vitro and in Vivo Interactions with Established Drugs
The Bcl-2 Homology Domain 3 Mimetic ABT-737 Targets the Apoptotic Machinery in Acute Lymphoblastic Leukemia Resulting in Synergistic in Vitro and in Vivo Interactions with Established Drugs
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DOI：
10.1124/mol.109.060780
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发表时间：
2010-03-01
影响因子：
3.6
通讯作者：
Lock, Richard B.
中科院分区：
文献类型：
--
作者：
High, Laura M.;Szymanska, Barbara;Lock, Richard B.
抗细胞凋亡的Bcl2蛋白在包括白血病在内的许多癌症中过表达，并经常与常规化疗药物的耐药性有关。ABT-737是一种Bcl2同源结构域3的模拟物(结构见Natural 435：677-681,2005)，它抑制Bcl2、BclX-L和Bclw的生存功能。我们证明ABT-737作为单一药物对一组儿科急性淋巴细胞白血病(ALL)异种移植是有效的，这些移植是从免疫缺陷小鼠的患者活检中建立的。尽管白血病细胞株的体外耐药性与生存蛋白Mcl-1的表达有关，但Mcl-1的表达与体内对ABT-737的异种移植反应无关。然而，促凋亡蛋白Bim的表达及其与Bcl2的关联程度与体内ABT-737的敏感性显著相关。ABT737增强了L-天冬酰胺酶、拓扑替康、长春新碱和依托泊苷对耐药异种移植瘤的体内外抗白血病作用。最后，我们发现，L-天冬酰胺酶(通过特异性下调Mcl-1蛋白水平)、拓扑替康(通过DNA损伤激活P53)和ABT-737(通过抑制抗凋亡的Bcl2家族成员)在体外和体内都产生了显著的协同抗白血病效果。合理靶向凋亡通路的特定成分可能是改善难治性或复发性儿童急性淋巴细胞白血病治疗的有效途径。总体而言，这项研究支持将ABT-737的临床衍生物ABT-263(结构见癌症研究报告68：3421-3428,2008)纳入治疗复发/难治性儿童ALL的临床试验。
Antiapoptotic Bcl-2 proteins are overexpressed in a number of cancers, including leukemias, and are frequently associated with resistance to conventional chemotherapeutic drugs. ABT-737, a Bcl-2 homology domain 3 mimetic (for structure, see Nature 435: 677-681, 2005) inhibits the prosurvival function of Bcl-2, Bcl-X-L, and Bcl-w. We show that ABT-737 was effective as a single agent against a panel of pediatric acute lymphoblastic leukemia (ALL) xenografts, previously established, from patient biopsies, in immunodeficient mice. Although in vitro resistance of leukemia cell lines correlated with expression of the prosurvival protein Mcl-1, there was no relationship between Mcl-1 expression and in vivo xenograft response to ABT-737. However, expression of the proapoptotic protein Bim, and the extent of its association with Bcl-2, significantly correlated with in vivo ABT-737 sensitivity. ABT-737 potentiated the antileukemic effects of L-asparaginase, topotecan, vincristine, and etoposide against drug-resistant xenografts in vitro and in vivo. Finally, we show that the combination of L-asparaginase (by specifically down-regulating Mcl-1 protein levels), topotecan (by activating p53 via DNA damage), and ABT-737 (by inhibiting antiapoptotic Bcl-2 family members) caused profound synergistic antileukemic efficacy both in vitro and in vivo. Rational targeting of specific components of the apoptotic pathway may be a useful approach to improve the treatment of refractory or relapsed pediatric ALL. Overall, this study supports the inclusion of the clinical derivative of ABT-737, ABT-263 (for structure, see Cancer Res 68: 3421-3428, 2008), into clinical trials against relapsed/refractory pediatric ALL.