Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
Clin Cancer Res. 2010 Dec 1;16(23):5679-91. doi: 10.1158/1078-0432.CCR-10-1565.
To investigate the in vivo antitumor efficacy of quercetin in U937 xenografts and the functional roles of Mcl-1 and Bax in quercetin-induced apoptosis in human leukemia.
Leukemia cells were treated with quercetin, after which apoptosis, Mcl-1 expression, and Bax activation and translocation were evaluated. The efficacy of quercetin as well as Mcl-1 expression and Bax activation were investigated in xenografts of U937 cells.
Administration of quercetin caused pronounced apoptosis in both transformed and primary leukemia cells but not in normal blood peripheral mononuclear cells. Quercetin-induced apoptosis was accompanied by Mcl-1 downregulation and Bax conformational change and mitochondrial translocation that triggered cytochrome c release. Knockdown of Bax by siRNA reversed quercetin-induced apoptosis and abrogated the activation of caspase and apoptosis. Ectopic expression of Mcl-1 attenuated quercetin-mediated Bax activation, translocation, and cell death. Conversely, interruption of Mcl-1 by siRNA enhanced Bax activation and translocation, as well as lethality induced by quercetin. However, the absence of Bax had no effect on quercetin-mediated Mcl-1 downregulation. Furthermore, in vivo administration of quercetin attenuated tumor growth in U937 xenografts. The TUNEL-positive apoptotic cells in tumor sections increased in quercetin-treated mice as compared with controls. Mcl-1 downregulation and Bax activation were also observed in xenografts.
These data suggest that quercetin may be useful for the treatment of leukemia by preferentially inducing apoptosis in leukemia versus normal hematopoietic cells through a process involving Mcl-1 downregulation, which, in turn, potentiates Bax activation and mitochondrial translocation, culminating in apoptosis.
研究槲皮素在 U937 异种移植瘤中的体内抗肿瘤疗效，以及 Mcl-1 和 Bax 在槲皮素诱导人白血病细胞凋亡中的功能作用。
用槲皮素处理白血病细胞，然后评估细胞凋亡、Mcl-1 表达、Bax 激活和转位。在 U937 细胞的异种移植瘤中研究了槲皮素的疗效以及 Mcl-1 表达和 Bax 激活。
槲皮素给药导致转化和原发性白血病细胞明显凋亡，但对正常外周血单核细胞无影响。槲皮素诱导的凋亡伴随着 Mcl-1 下调和 Bax 构象变化以及线粒体转位，导致细胞色素 c 释放。siRNA 下调 Bax 逆转了槲皮素诱导的凋亡，并阻断了 caspase 的激活和凋亡。Mcl-1 的异位表达减弱了槲皮素介导的 Bax 激活、转位和细胞死亡。相反，siRNA 中断 Mcl-1 增强了 Bax 的激活和转位，以及槲皮素诱导的致死性。然而，Bax 的缺失对槲皮素介导的 Mcl-1 下调没有影响。此外，体内给予槲皮素可减轻 U937 异种移植瘤的生长。与对照组相比，槲皮素处理的小鼠肿瘤切片中 TUNEL 阳性凋亡细胞增加。在异种移植瘤中也观察到 Mcl-1 下调和 Bax 激活。
这些数据表明，槲皮素通过下调 Mcl-1，进而增强 Bax 激活和线粒体转位，最终导致凋亡，可能有助于治疗白血病，因为它优先诱导白血病而非正常造血细胞凋亡。
