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CHEMOTHERAPY, 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

Department of Biochemistry, Trinity College, Dublin, Ireland (M.M.M.G., L.M.G., S.L., D.C.W., D.M.Z.); Dipartimento Farmaco Chimico Tecnologico, Universita'delgi Studi di Siena, Siena, Italy (G.C., V.N.); and Department of Hematology, Institute of Molecular Medicine, Trinity Centre, St. James's Hospital, Dublin, Ireland (M.L.)

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.

Address correspondence to: Dr. Daniela Zisterer, Department of Biochemistry, Trinity College, Dublin 2, Ireland. E-mail: dzistrer{at}tcd.ie

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