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-x(L) 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.
Original language | English |
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Pages (from-to) | 288-97 |
Number of pages | 10 |
Journal | The Journal of pharmacology and experimental therapeutics |
Volume | 321 |
Issue number | 1 |
DOIs | |
Publication status | Published - Apr 2007 |
Keywords
- Apoptosis
- Benzamides
- Blotting, Western
- Cell Cycle
- Cell Line, Tumor
- Cell Survival
- Down-Regulation
- Drug Resistance, Neoplasm
- Drug Synergism
- Fusion Proteins, bcr-abl
- HL-60 Cells
- Humans
- K562 Cells
- Leukemia, Myeloid
- Microtubules
- Monocytes
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasm Proteins
- Oxazepines
- Piperazines
- Poly(ADP-ribose) Polymerases
- Proto-Oncogene Proteins c-bcl-2
- Pyrimidines
- Pyrroles
- bcl-X Protein