3, 3′-diindolylmethane exhibits antileukemic activity in vitro and in vivo through a akt-dependent process3、3u2032-diindolylmethane展品antileukemic活动通过akt-dependent体外和体内过程.pdfVIP

3, 39-Diindolylmethane Exhibits Antileukemic Activity In Vitro and In Vivo through a Akt-Dependent Process 1,2 2 2 1 3 1 3 Ning Gao *, Senping Cheng , Amit Budhraja , E-Hu Liu , Jieping Chen , Deying Chen , Zailin Yang , Jia 4 2 2 Luo , Xianglin Shi , Zhuo Zhang * 1 Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China, 2 Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America, 3 Department of Hematology, Southwest Hospital, 3rd Military Medical University, Chongqing, China, 4 Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, United States of America Abstract 3,39-diindolylmethane (DIM), one of the active products derived from Brassica plants, is a promising antitumor agent. The present study indicated that DIM significantly induced apoptosis in U937 human leukemia cells in dose- and time- dependent manners. These events were also noted in other human leukemia cells (Jurkat and HL-60) and primary human leukemia cells (AML) but not in normal bone marrow mononuclear cells. We also found that DIM-induced lethality is associated with caspases activation, myeloid cell leukemia-1 (Mcl-1) down-regulation, p21cip1/waf1 up-regulation, and Akt inactivation accompanied by c-jun NH2-terminal kinase (JNK) activation. Enforced activation of Akt by a constitutively active Akt construct prevented DIM-mediated caspase activation, Mcl-1 down-regulation, JNK activation, and apoptosis. Conversely, DIM lethality was potentiated by the PI3K inhibitor LY294002. Interruption of the JN