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Identification of Tubulin as the Molecular Target of Proapoptotic Pyrrolo-1,5-benzoxazepines

School of Biochemistry and Immunology, Trinity College, Dublin, Ireland (J.M.M., L.M.G., S.C., V.O., D.C.W., D.M.Z.); Conway Institute of Molecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland (M.M.M.); Dipartimento Farmaco Chimico Tecnologico, Universita' degli Studi di Siena, Siena, Italy (G.C., C.F.); and the Institute of Molecular Medicine, St James's Hospital and Trinity College, Dublin, Ireland (M.L.)

We have demonstrated previously that certain members of a series of novel pyrrolo-1,5-benzoxazepine (PBOX) compounds potently induce apoptosis in a variety of human chemotherapy-resistant cancer cell lines and in primary ex vivo material derived from cancer patients. A better understanding of the molecular mechanisms underlying the apoptotic effects of these PBOX compounds is essential to their development as antineoplastic therapeutic agents. This study sought to test the hypothesis that proapoptotic PBOX compounds target the microtubules. We show that a representative proapoptotic PBOX compound, PBOX-6, induces apoptosis in both the MCF-7 and K562 cell lines. An accumulation of cells in G₂/M precedes apoptosis in response to PBOX-6. PBOX-6 induces prometaphase arrest and causes an accumulation of cyclin B₁ levels and activation of cyclin B₁/CDK1 kinase in a manner similar to that of two representative antimicrotubule agents, nocodazole and paclitaxel. Indirect immunofluorescence demonstrates that both PBOX-6 and another pro-apoptotic PBOX compound, PBOX-15, cause microtubule depolymerization in MCF-7 cells. They also inhibit the assembly of purified tubulin in vitro, whereas a nonapoptotic PBOX compound (PBOX-21) has no effect on either the cellular microtubule network or on the assembly of purified tubulin. This suggests that the molecular target of the pro-apoptotic PBOX compounds is tubulin. PBOX-6 does not bind to either the vinblastine or the colchicine binding site on tubulin, suggesting that it binds to an as-yet-uncharacterised novel site on tubulin. The ability of PBOX-6 to bind tubulin and cause microtubule depolymerization confirms it as a novel candidate for antineoplastic therapy.

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

This article has been cited by other articles:

				L. M. Greene, G. Campiani, M. Lawler, D. C. Williams, and D. M. Zisterer BubR1 Is Required for a Sustained Mitotic Spindle Checkpoint Arrest in Human Cancer Cells Treated with Tubulin-Targeting Pyrrolo-1,5-Benzoxazepines Mol. Pharmacol., February 1, 2008; 73(2): 419 - 430. [Abstract] [Full Text] [PDF]

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