title: 3,3'-Diindolylmethane exhibits antileukemic activity in vitro and in vivo through a Akt-dependent process.
abstract: 3,3'-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, p21(cip1/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 JNK pathway by pharmacologic or genetic approaches attenuated DIM-induced caspases activation, Mcl-1 down-regulation, and apoptosis. Lastly, DIM inhibits tumor growth of mouse U937 xenograft, which was related to induction of apoptosis and inactivation of Akt, as well as activation of JNK. Collectively, these findings suggest that DIM induces apoptosis in human leukemia cell lines and primary human leukemia cells, and exhibits antileukemic activity in vivo through Akt inactivation and JNK activation.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China. gaoning59@yahoo.com.cn
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.forename: Senping
authors.initials: S
authors.lastname: Cheng
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: E-Hu
authors.initials: EH
authors.lastname: Liu
authors.forename: Jieping
authors.initials: J
authors.lastname: Chen
authors.forename: Deying
authors.initials: D
authors.lastname: Chen
authors.forename: Zailin
authors.initials: Z
authors.lastname: Yang
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020169:Caspases; D002867:Chromones; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D048031:JNK Mitogen-Activated Protein Kinases; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; C579094:Mcl1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C016392:3,3'-diindolylmethane