RRC ID 65167
Author Patel V, Balakrishnan K, Keating MJ, Wierda WG, Gandhi V.
Title Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells.
Journal Blood
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.
Volume 125(7)
Pages 1126-36
Published 2015-2-12
DOI 10.1182/blood-2014-01-546796
PII S0006-4971(20)35274-5
PMID 25538042
PMC PMC4326772
MeSH Animals B-Lymphocytes / drug effects B-Lymphocytes / physiology Caspases, Effector / genetics* Caspases, Effector / metabolism* Cell Death / drug effects Cells, Cultured Embryo, Mammalian Enzyme Activation / drug effects Gene Expression Regulation, Enzymologic Humans Hydrazones / pharmacology* Jurkat Cells Leukemia, Lymphocytic, Chronic, B-Cell / enzymology* Leukemia, Lymphocytic, Chronic, B-Cell / pathology Leukocytes, Mononuclear / drug effects Leukocytes, Mononuclear / physiology Mice Piperazines / pharmacology* Protein Precursors / genetics Protein Precursors / metabolism Zinc / pharmacology
IF 17.794
Human and Animal Cells StromaNKtert(RCB2350)