title: Endoplasmic reticulum stress associated with caspases-4 and -2 mediates korbazol-induced B-chronic lymphocytic leukemia cell apoptosis.
abstract: OBJECTIVE
  B-cell chronic lymphocytic leukemia (B-CLL) is an incurable disease that rapidly develops drug resistance. Therefore there is a need for identifying new agents that will improve the therapeutic outcome. Korbazol is a natural product known to exert cytotoxic effect on the in vitro survival of leukemic cells. The aim of this study was to investigate the mechanism of korbazol-induced apoptosis in B-CLL leukemic cells.
  
  
  METHODS
  peripheral blood mononuclear cells from 10 B-CLL patients were used for assessing the effect of caspase inhibitors and chelator of intracellular Ca(2)+.
  
  
  RESULTS
  cell death rate induced by the tested compound was decreased with the caspase-3 inhibitor Ac-DEVD-CHO, and the inhibitors of caspase-2 (Z-VDVAD-FMK) and -4 (ZYVAD- FMK), but not with the caspase-9 inhibitor z-LEHD-FMK and caspase-8 inhibitor z-IETD-FMK. No significant release of cytochrome C (cyt C) from mitochondria to the cytosol of B-CLL cells treated with korbazol was observed. Moreover, chelating of intracellular Ca(2)+ with BAPTA-AM almost completely abolished the cytotoxic effect of korbazol.
  
  
  CONCLUSIONS
  engagement of caspases-2 and -4 and mobilization of intracellular Ca(2)+ indicate involvement of endoplasmic reticulum (ER) stress in apoptosis induced by korbazol.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Medicine, University of Kragujevac, Kragujevac, Serbia. suza_popovic@yahoo.com
authors.forename: S
authors.initials: S
authors.lastname: Popovic
authors.forename: D
authors.initials: D
authors.lastname: Baskic
authors.forename: P
authors.initials: P
authors.lastname: Djurdjevic
authors.forename: I
authors.initials: I
authors.lastname: Zelen
authors.forename: M
authors.initials: M
authors.lastname: Mitrovic
authors.forename: I
authors.initials: I
authors.lastname: Nikolic
authors.forename: D
authors.initials: D
authors.lastname: Avramovic
authors.forename: M
authors.initials: M
authors.lastname: Radenkovic
authors.forename: N
authors.initials: N
authors.lastname: Arsenijevic
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001688:Biological Products / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D053143:Caspase 2 / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; C556112:Korbazol; D010936:Plant Extracts; D045304:Cytochromes c; C093516:CASP4 protein, human; D053143:Caspase 2; D053471:Caspases, Initiator; D002118:Calcium