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, Daniela M Zisterer, Mark Lawler

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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 languageEnglish
Pages (from-to)288-97
Number of pages10
JournalThe Journal of pharmacology and experimental therapeutics
Volume321
Issue number1
DOIs
Publication statusPublished - 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

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