Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells

S. H. Inayat-Hussain, S. M. McGuinness, R. Johansson, J. Lundstrom, D. Ross

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    Abstract

    The hydroquinone and catechol like metabolites, NCQ344 and NCQ436 respectively, of the antipsychotic remoxipride have recently been demonstrated to induce apoptosis in myeloperoxidase (MPO)-rich human bone marrow progenitor and HL-60 cells [S.M. McGuinness, R. Johansson, J. Lundstrom, D. Ross, Induction of apoptosis by remoxipride metabolites in HL- 60 and CD34+/CD19 - human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia, Chem. Biol. Interact. 121 (1999) 253- 265]. In the present study, we determined the molecular mechanisms of apoptosis induced by these remoxipride metabolites in HL-60 cells. Our results show that apoptosis was accompanied by phosphatidylserine (PS) exposure, activation of caspases-9, -3, -7 and DNA cleavage. In HL-60 cells treated with the hydroquinone NCQ344 and catechol NCQ436, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp.fluoromethyl ketone (Z-VAD.FMK) blocked DNA cleavage and activation of caspases-9, -3/-7. In addition, PS exposure was significantly but not completely inhibited by Z-VAD.FMK. These results demonstrate that although Z-VAD.FMK inhibitable caspases are necessary for maximal apoptosis induced by NCQ344 and NCQ436, additional caspase-independent processes may orchestrate changes leading to PS exposure during apoptosis induced by the remoxipride polyphenolic metabolites. (C) 2000 Elsevier Science Ireland Ltd.

    Original languageEnglish
    Pages (from-to)51-63
    Number of pages13
    JournalChemico-Biological Interactions
    Volume128
    Issue number1
    DOIs
    Publication statusPublished - 15 Aug 2000

    Fingerprint

    Remoxipride
    HL-60 Cells
    Caspases
    Metabolites
    Apoptosis
    Phosphatidylserines
    DNA Cleavage
    Caspase 9
    Caspase 3
    Bone
    Chemical activation
    Caspase Inhibitors
    Aplastic Anemia
    DNA
    Ketones
    Bone Marrow Cells
    Antipsychotic Agents
    Peroxidase
    hydroquinone
    catechol

    Keywords

    • Apoptosis
    • Caspases
    • Catechol
    • Hydroquinone
    • Remoxipride

    ASJC Scopus subject areas

    • Toxicology

    Cite this

    Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells. / Inayat-Hussain, S. H.; McGuinness, S. M.; Johansson, R.; Lundstrom, J.; Ross, D.

    In: Chemico-Biological Interactions, Vol. 128, No. 1, 15.08.2000, p. 51-63.

    Research output: Contribution to journalArticle

    Inayat-Hussain, S. H. ; McGuinness, S. M. ; Johansson, R. ; Lundstrom, J. ; Ross, D. / Caspase-dependent and -independent mechanisms in apoptosis induced by hydroquinone and catechol metabolites of remoxipride in HL-60 cells. In: Chemico-Biological Interactions. 2000 ; Vol. 128, No. 1. pp. 51-63.
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    AU - Inayat-Hussain, S. H.

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    AU - Ross, D.

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    N2 - The hydroquinone and catechol like metabolites, NCQ344 and NCQ436 respectively, of the antipsychotic remoxipride have recently been demonstrated to induce apoptosis in myeloperoxidase (MPO)-rich human bone marrow progenitor and HL-60 cells [S.M. McGuinness, R. Johansson, J. Lundstrom, D. Ross, Induction of apoptosis by remoxipride metabolites in HL- 60 and CD34+/CD19 - human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia, Chem. Biol. Interact. 121 (1999) 253- 265]. In the present study, we determined the molecular mechanisms of apoptosis induced by these remoxipride metabolites in HL-60 cells. Our results show that apoptosis was accompanied by phosphatidylserine (PS) exposure, activation of caspases-9, -3, -7 and DNA cleavage. In HL-60 cells treated with the hydroquinone NCQ344 and catechol NCQ436, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp.fluoromethyl ketone (Z-VAD.FMK) blocked DNA cleavage and activation of caspases-9, -3/-7. In addition, PS exposure was significantly but not completely inhibited by Z-VAD.FMK. These results demonstrate that although Z-VAD.FMK inhibitable caspases are necessary for maximal apoptosis induced by NCQ344 and NCQ436, additional caspase-independent processes may orchestrate changes leading to PS exposure during apoptosis induced by the remoxipride polyphenolic metabolites. (C) 2000 Elsevier Science Ireland Ltd.

    AB - The hydroquinone and catechol like metabolites, NCQ344 and NCQ436 respectively, of the antipsychotic remoxipride have recently been demonstrated to induce apoptosis in myeloperoxidase (MPO)-rich human bone marrow progenitor and HL-60 cells [S.M. McGuinness, R. Johansson, J. Lundstrom, D. Ross, Induction of apoptosis by remoxipride metabolites in HL- 60 and CD34+/CD19 - human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia, Chem. Biol. Interact. 121 (1999) 253- 265]. In the present study, we determined the molecular mechanisms of apoptosis induced by these remoxipride metabolites in HL-60 cells. Our results show that apoptosis was accompanied by phosphatidylserine (PS) exposure, activation of caspases-9, -3, -7 and DNA cleavage. In HL-60 cells treated with the hydroquinone NCQ344 and catechol NCQ436, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp.fluoromethyl ketone (Z-VAD.FMK) blocked DNA cleavage and activation of caspases-9, -3/-7. In addition, PS exposure was significantly but not completely inhibited by Z-VAD.FMK. These results demonstrate that although Z-VAD.FMK inhibitable caspases are necessary for maximal apoptosis induced by NCQ344 and NCQ436, additional caspase-independent processes may orchestrate changes leading to PS exposure during apoptosis induced by the remoxipride polyphenolic metabolites. (C) 2000 Elsevier Science Ireland Ltd.

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