期刊
BLOOD
卷 119, 期 24, 页码 5807-5816出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-12-400929
关键词
-
类别
资金
- Australian Research Council
- Australian National Health and Medical Research Council (NHMRC) [461219, 461221, 637326]
- Lady Tata Memorial Trust
- Leukemia Foundation of Australia
- Cancer Council Victoria
- Leukemia & Lymphoma Society (SCOR grant) [7413]
- National Cancer Institute [CA43540]
The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-x(L), and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-x(L) predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-x(L) or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-x(L)/Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies. (Blood. 2012; 119(24):5807-5816)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据