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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

STI-571 (Imatinib Mesylate) Enhances the Apoptotic Efficacy of Pyrrolo-1,5-Benzoxazepine-6, a Novel Microtubule-Targeting Agent, in Both STI-571-Sensitive and -Resistant Bcr-Abl-Positive Human Chronic Myeloid Leukemia Cells

Lisa M. Greene, Liam Kelly, Valeria Onnis, Giuseppe Campiani, Mark Lawler, D. Clive Williams and Daniela M. Zisterer
Journal of Pharmacology and Experimental Therapeutics April 2007, 321 (1) 288-297; DOI: https://doi.org/10.1124/jpet.106.116640
Lisa M. Greene
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Liam Kelly
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Valeria Onnis
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Giuseppe Campiani
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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

Interactions between the Bcr-Abl kinase inhibitor STI-571 (imatinib mesylate) and a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-6, were investigated in STI-571-sensitive and -resistant human chronic myeloid leukemia (CML) cells. Cotreatment of PBOX-6 with STI-571 induced significantly more apoptosis in Bcr-Abl-positive CML cell lines (K562 and LAMA-84) than either drug alone (P < 0.01). Cell cycle analysis of propidium iodide-stained cells showed that STI-571 significantly reduced PBOX-6-induced G2M arrest and polyploid formation with a concomitant increase in apoptosis. Similar results were obtained in K562 CML cells using lead MTAs (paclitaxel and nocodazole) in combination with STI-571. Potentiation of PBOX-6-induced apoptosis by STI-571 was specific to Bcr-Abl-positive leukemia cells with no cytoxic effects observed on normal peripheral blood cells. The combined treatment of STI-571 and PBOX-6 was associated with the down-regulation of Bcr-Abl and repression of proteins involved in Bcr-Abl transformation, namely the antiapoptotic proteins Bcl-xL and Mcl-1. Importantly, PBOX-6/STI-571 combinations were also effective in STI-571-resistant cells. Together, these findings highlight the potential clinical benefits in simultaneously targeting the microtubules and the Bcr-Abl oncoprotein in STI-571-sensitive and -resistant CML cells.

Footnotes

  • This work was supported by Science Foundation Ireland

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

  • doi:10.1124/jpet.106.116640.

  • ABBREVIATIONS: CML, chronic myeloid leukemia; STI-571, imatinib mesylate; PBOX, pyrrolo-1,5-benzoxazepine; MTA, microtubule-targeting agent; CDKI, cyclin-dependent kinase inhibitor; 4N, tetraploid; PARP, poly(ADP-ribose) polymerase; FBS, fetal bovine serum; DMSO, dimethyl sulfoxide; mAb, monoclonal antibody; PBS, phosphate-buffered saline; TBS-T, Tris-buffered saline, pH 7.6/0.05% Tween 20; RT, room temperature; PI, propidium iodide; MTT, 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide; 2N, diploid; PD173955, pyrido[2,3-d]pyrimidine Src tyrosine kinase inhibitor.

    • Received November 3, 2006.
    • Accepted December 29, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 368 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 368, Issue 3
1 Mar 2019
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STI-571 (Imatinib Mesylate) Enhances the Apoptotic Efficacy of Pyrrolo-1,5-Benzoxazepine-6, a Novel Microtubule-Targeting Agent, in Both STI-571-Sensitive and -Resistant Bcr-Abl-Positive Human Chronic Myeloid Leukemia Cells
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

STI-571 (Imatinib Mesylate) Enhances the Apoptotic Efficacy of Pyrrolo-1,5-Benzoxazepine-6, a Novel Microtubule-Targeting Agent, in Both STI-571-Sensitive and -Resistant Bcr-Abl-Positive Human Chronic Myeloid Leukemia Cells

Lisa M. Greene, Liam Kelly, Valeria Onnis, Giuseppe Campiani, Mark Lawler, D. Clive Williams and Daniela M. Zisterer
Journal of Pharmacology and Experimental Therapeutics April 1, 2007, 321 (1) 288-297; DOI: https://doi.org/10.1124/jpet.106.116640

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

STI-571 (Imatinib Mesylate) Enhances the Apoptotic Efficacy of Pyrrolo-1,5-Benzoxazepine-6, a Novel Microtubule-Targeting Agent, in Both STI-571-Sensitive and -Resistant Bcr-Abl-Positive Human Chronic Myeloid Leukemia Cells

Lisa M. Greene, Liam Kelly, Valeria Onnis, Giuseppe Campiani, Mark Lawler, D. Clive Williams and Daniela M. Zisterer
Journal of Pharmacology and Experimental Therapeutics April 1, 2007, 321 (1) 288-297; DOI: https://doi.org/10.1124/jpet.106.116640
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