title: A novel bisindolymaleimide derivative (WK234) inhibits proliferation and induces apoptosis through the protein kinase Cβ pathway, in chronic myelogenous leukemia K562 cells.
abstract: WK234, a novel bisindolymaleimide derivative, was designed as a protein kinase Cβ (PKCβ) inhibitor. The objective of this study was to evaluate the anti-tumor activity of WK234 in the human chronic myelogenous leukemia (CML) K562 cell line and to investigate possible mechanisms of its action. The results show that WK234 inhibited K562 cell proliferation in a time- and dose-dependent manner. WK234 increased cytochrome C release and caspase-3 cleavage, which indicates that it induced apoptosis via mitochondria- and caspase-mediated pathways. Western blotting showed that PKCβ1, PKCβ2, and their phosphorylation levels were effectively decreased after 2-4 h of WK234 treatment. Meanwhile the phosphorylation status of PKCβ downstream proteins, glycogen synthase kinase 3α/β (GSK3α/β) and extracellular signal-regulated kinase (ERK), were inhibited. WK234 blocked phorbol myristate acetate (PMA)-induced Ser(660) phosphorylation of PKCβ2 located at the cell membrane, and increased Ser(660) PKCβ2 expression within the cytoplasm and the nucleus. These results indicate that WK234 inhibited cell proliferation and induced apoptosis through suppressing the PKCβ signal pathway. WK234 might be a promising candidate for the treatment of CML.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Xiang-Yan
authors.initials: XY
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Yuan
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhan-Zhu
authors.initials: ZZ
authors.lastname: Liu
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; C561686:WK234 compound; D011493:Protein Kinase C; D064546:Protein Kinase C beta