title: Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells.
abstract: Intrinsic and extrinsic apoptotic pathways converge to activate common downstream executioner caspases (caspase-3, -6, and -7), resulting in cell death. In chronic lymphocytic leukemia (CLL), neoplastic B cells evade apoptosis owing to the overexpression of survival proteins. We hypothesized that direct activation of procaspases could bypass the apoptosis resistance induced by the upstream prosurvival proteins. The procaspase-activating compounds (PAC-1), including B-PAC-1 (L14R8), convert inactive executioner procaspases to their active cleaved forms by chelation of labile zinc ions. Both at transcript and protein levels, primary CLL cells express high levels of latent procaspases (3, -7, and -9). B-PAC-1 treatment induced CLL lymphocyte death which was higher than that in normal peripheral blood mononuclear cells or B cells, and was independent of prognostic markers and microenvironmental factors. Mechanistically, B-PAC-1 treatment activated executioner procaspases and not other Zn-dependent enzymes. Exogenous zinc completely, and pancaspase inhibitors partially, reversed B-PAC-1-induced apoptosis, elucidating the zinc-mediated mechanism of action. The cell demise relied on the presence of caspase-3/7 but not caspase-8 or Bax/Bak proteins. B-PAC-1 in combination with an inhibitor of apoptosis protein antagonist (Smac066) synergistically induced apoptosis in CLL samples. Our investigations demonstrated that direct activation of executioner procaspases via B-PAC-1 treatment bypasses apoptosis resistance and is a novel approach for CLL therapeutics.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX; and.
authors.forename: Viralkumar
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX; and Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D053470:Caspases, Effector / Q000235:genetics* / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; C000597017:2-(4-(4-(benzyloxy)benzyl)piperazin-1-yl)-N'-(3,5-di-tert-butyl-2-hydroxybenzylidene)acetohydrazide; D006835:Hydrazones; D010879:Piperazines; D011498:Protein Precursors; D053470:Caspases, Effector; D015032:Zinc