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
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This work was supported by Science Foundation Ireland
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.116640.
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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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