ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation
ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation
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DOI：
10.1016/j.bcp.2013.01.011
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发表时间：
2013-04-01
影响因子：
5.8
通讯作者：
Russo, Gian Luigi
中科院分区：
文献类型：
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作者：
Russo, Maria;Spagnuolo, Carmela;Russo, Gian Luigi
慢性淋巴细胞白血病（CLL）是成人人群中最常见的白血病形式，尽管有许多研究，但它被认为是一种无法治愈的疾病。由于CLL的特点是促生存Bcl-2家族成员的过表达，因此使用它们的拮抗剂（如ABT-737）治疗是一种很有前途的新治疗策略。ABT-737是一种模拟BH3的药物，与Bcl-2、Bcl-X-L和Bcl-w具有高亲和力，与Mcl-1和Bfl-1的相互作用较弱。先前的研究表明，当与死亡配体或氟达拉宾相关时，槲皮素（一种天然存在于食品和饮料中的类黄酮）能够通过Mcl-1下调的机制使CLL患者分离的b细胞对凋亡敏感。在这里，我们报告了ABT-737和槲皮素之间的关联协同诱导b细胞和五种白血病细胞系的凋亡（组合指数）
Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatments with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-X-L and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index