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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.

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.
AuthorsMargaret M Mc Gee, Lisa M Greene, Susan Ledwidge, Giuseppe Campiani, Vito Nacci, Mark Lawler, D Clive Williams, Daniela M Zisterer
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 310 Issue 3 Pg. 1084-95 (Sep 2004) ISSN: 0022-3565 [Print] United States
PMID15143129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • BCL2L1 protein, human
  • CEP-11004
  • Carbazoles
  • Indoles
  • MAS1 protein, human
  • Oxazepines
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Dactinomycin
  • Etoposide
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • PBOX-6
Topics
  • Antibiotics, Antineoplastic (pharmacology)
  • Antineoplastic Agents (pharmacology)
  • Apoptosis
  • Carbazoles (pharmacology)
  • Dactinomycin (pharmacology)
  • Drug Resistance, Neoplasm
  • Etoposide (pharmacology)
  • Humans
  • Indoles (pharmacology)
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells
  • K562 Cells
  • Leukemia (pathology)
  • Leukocytes, Mononuclear (cytology, drug effects)
  • Mitogen-Activated Protein Kinases (metabolism)
  • Oxazepines (pharmacology)
  • Phosphorylation (drug effects)
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
  • Pyrroles (pharmacology)
  • Subcellular Fractions
  • Tumor Cells, Cultured
  • Ultraviolet Rays
  • bcl-2-Associated X Protein
  • bcl-X Protein

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