Differential involvement of caspases in hydroquinone-induced apoptosis in human leukemic hl-60 and jurkat cells.
The benzene metabolite hydroquinone (HQ) is postulated to exert its myelotoxicity by bioactivation to reactive quinone derivatives in myeloperoxidase (MPO)-containing cells. In this study, the role of caspases in hydroquinone-induced apoptosis in MPO-rich HL-60 promyelocytic leukemia and MPO-deficient Jurkat T-lymphoblastic leukemia cells was investigated. HQ-induced apoptosis in both cell types was accompanied by phosphatidylserine (PS) exposure, caspases-3/-7 activation, PARP cleavage, DNA fragmentation, and ultrastructural changes as assessed by electron microscopy. In HL-60 cells, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD.FMK) blocked activation of caspases-3/-7, cleavage of PARP, and DNA, but PS externalization and cytoplasmic changes were not significantly affected. In marked contrast, all features of apoptosis were completely inhibited by Z-VAD.FMK in HQ-treated Jurkat cells. These data provide evidence for Z-VAD.FMK-insensitive and caspases-3/-7-independent pathway(s) in the externalization of PS and cytoplasmic changes during HQ-induced apoptosis in HL-60 cells. In contrast, in Jurkat cells, all of these changes required caspase activation. The ability of HQ to induce equivalent apoptosis in both MPO-deficient Jurkat cells and MPO-rich HL-60 cells demonstrates that MPO-catalyzed bioactivation of HQ is not a prerequisite for toxicity. The differential mechanisms of apoptosis in HL-60 and Jurkat T cells may reflect the MPO activity of these cells and, as a result, the amount of reactive BQ and other metabolites that are generated.
Inayat-Hussain
S H
SH
Molecular Toxicology and Environmental Health Sciences Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. salmann@medic.ukm.my
Winski
S L
SL
Ross
D
D
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D019169:Jurkat Cells / Q000187:drug effects* / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D000975:Antioxidants; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006873:Hydroquinones; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D009195:Peroxidase; D020169:Caspases; C031927:hydroquinone