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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH2-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-XL

Margaret M. Mc Gee, Lisa M. Greene, Susan Ledwidge, Giuseppe Campiani, Vito Nacci, Mark Lawler, D. Clive Williams and Daniela M. Zisterer
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 1084-1095; DOI: https://doi.org/10.1124/jpet.104.067561
Margaret M. Mc Gee
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Lisa M. Greene
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Susan Ledwidge
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Giuseppe Campiani
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Vito Nacci
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Mark Lawler
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D. Clive Williams
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Daniela M. Zisterer
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Abstract

Overexpression of the Bcl-2 proto-oncogene in tumor cells confers resistance against chemotherapeutic drugs. In this study, we describe how the novel pyrrolo-1,5-benzoxazepine compound 7-[{dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) selectively induces apoptosis in Bcl-2-overexpressing cancer cells, whereas it shows no cytotoxic effect on normal peripheral blood mononuclear cells. PBOX-6 overcomes Bcl-2-mediated resistance to apoptosis in chronic myelogenous leukemia (CML) K562 cells by the time- and dose-dependent phosphorylation and inactivation of antiapoptotic Bcl-2 family members Bcl-2 and Bcl-XL. PBOX-6 also induces Bcl-2 phosphorylation and apoptosis in wild-type T leukemia CEM cells and cells overexpressing Bcl-2. This is in contrast to chemotherapeutic agents such as etoposide, actinomycin D, and ultraviolet irradiation, whereby overexpression of Bcl-2 confers resistance against apoptosis. In addition, PBOX-6 induces Bcl-2 phosphorylation and apoptosis in wild-type Jurkat acute lymphoblastic leukemia cells and cells overexpressing Bcl-2. However, Jurkat cells containing a Bcl-2 triple mutant, whereby the principal Bcl-2 phosphorylation sites are mutated to alanine, demonstrate resistance against Bcl-2 phosphorylation and apoptosis. PBOX-6 also induces the early and transient activation of c-Jun NH2-terminal kinase (JNK) in CEM cells. Inhibition of JNK activity prevents Bcl-2 phosphorylation and apoptosis, implicating JNK in the upstream signaling pathway leading to Bcl-2 phosphorylation. Collectively, these findings identify Bcl-2 phosphorylation and inactivation as a critical step in the apoptotic pathway induced by PBOX-6 and highlight its potential as an effective antileukemic agent.

Footnotes

  • This work was supported by BioResearch Ireland and Enterprise Ireland.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.104.067561.

  • ABBREVIATIONS: JNK, c-Jun NH2-terminal kinase; MLK, mixed lineage kinase; CML, chronic myelogenous leukemia; PBOX-6, 7-[{dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine; PBMC, peripheral blood mononuclear cell; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; GST, glutathione S-transferase; DMSO, dimethyl sulfoxide; IP, immunoprecipitation; PAGE, polyacrylamide gel electrophoresis; LDH, dehydrogenase.

    • Received February 25, 2004.
    • Accepted May 12, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH2-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-XL

Margaret M. Mc Gee, Lisa M. Greene, Susan Ledwidge, Giuseppe Campiani, Vito Nacci, Mark Lawler, D. Clive Williams and Daniela M. Zisterer
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1084-1095; DOI: https://doi.org/10.1124/jpet.104.067561

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH2-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-XL

Margaret M. Mc Gee, Lisa M. Greene, Susan Ledwidge, Giuseppe Campiani, Vito Nacci, Mark Lawler, D. Clive Williams and Daniela M. Zisterer
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1084-1095; DOI: https://doi.org/10.1124/jpet.104.067561
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