title: Phenethyl isothiocyanate exhibits antileukemic activity in vitro and in vivo by inactivation of Akt and activation of JNK pathways.
abstract: Effects of phenethyl isothiocyanate (PEITC) have been investigated in human leukemia cells (U937, Jurkat, and HL-60) as well as in primary human acute myeloid leukemia (AML) cells in relation to apoptosis and cell signaling events. Exposure of cells to PEITC resulted in pronounced increase in the activation of caspase-3, -8, -9, cleavage/degradation of PARP, and apoptosis in dose- and time-dependent manners. These events were accompanied by the caspase-independent downregulation of Mcl-1, inactivation of Akt, as well as activation of Jun N-terminal kinase (JNK). Inhibition of PI3K/Akt by LY294002 significantly enhanced PEITC-induced apoptosis. Conversely, enforced activation of Akt by a constitutively active Akt construct markedly abrogated PEITC-mediated JNK activation, Mcl-1 downregulation, caspase activation, and apoptosis, and also interruption of the JNK pathway by pharmacological or genetically (e.g., siRNA) attenuated PEITC-induced apoptosis. Finally, administration of PEITC markedly inhibited tumor growth and induced apoptosis in U937 xenograft model in association with inactivation of Akt, activation of JNK, as well as downregulation of Mcl-1. Taken together, these findings represent a novel mechanism by which agents targeting Akt/JNK/Mcl-1 pathway potentiate PEITC lethality in transformed and primary human leukemia cells and inhibitory activity of tumor growth of U937 xenograft model.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, III Military Medical University, Chongqing, China. gaoning59@yahoo.com.cn
authors.forename: N
authors.initials: N
authors.lastname: Gao
authors.forename: A
authors.initials: A
authors.lastname: Budhraja
authors.forename: S
authors.initials: S
authors.lastname: Cheng
authors.forename: E-H
authors.initials: EH
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Shi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D017879:Isothiocyanates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; C058305:phenethyl isothiocyanate; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases