The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate

Simona Gatto, Barbara Scappini, Lan Pham, Francesco Onida, Michele Milella, Greg Ball, Clara Ricci, Vladimir Divoky, Srdan Verstovsek, Hagop M. Kantarjian, Michael J. Keating, Jorge E. Cortes, Miloslav Beran

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Background and Objectives. Imatinib mesylate (IM) is the choice treatment for Bcr/Abl-positive malignancies. Emergence of resistance to IM warrants the exploration of novel well-tolerated anticancer agents. We intended to evaluate the effect of PS-341 on proliferation, survival, and cellular events in Bcr/Abl-positive cells sensitive and resistant to IM, and to investigate the effect of PS-341 and IM in conjunction. Design and Methods. Bcr/Abl-positive cell lines sensitive (p210Bcr/Abl KBM5, p210Bcr/Abl KBM7, and p190Bcr/Abl Z-119) or resistant (KBM5-R) to IM were treated with PS-341 alone or in combination with IM. The effect on cell growth was determined using the MTT assay. Cell-cycle analysis was performed by propidium iodide staining. Apoptosis was evaluated by measurement of sub-G1 DNA content, annexin V binding, and caspase 3 activity assays. Levels of apoptotic proteins, P-IkBα, Bcr/Abl, and phosphorylated Bcr/Abl were determined by western blotting. NF-kB activity was evaluated by electromobility gel shift assays. Results. PS-341 exerted growth inhibition effects in IM-sensitive and -resistant cells. This phenomenon correlated with accumulation of cells in the G2/M phase of cell cycle; transient downregulation of NFκB DNA binding activity; downregulation of Bcl-xL; activation of caspase 3, induction of apoptosis; inhibition of expression and phosphorylation of Bcr/Abl. Sequential combination of PS-341 followed by IM demonstrated a synergistic pro-apoptotic effect in IM-sensitive cells; concomitant exposure was antagonistic. Interpretation and Conclusions. PS-341 suppresses growth and induces apoptosis in Bcr/Abl-positive cells sensitive and resistant to IM. The use of PS-341 should be explored in patients with chronic myelogenous leukemia resistant to IM. Trials of combinations of PS-341 and IM require cautious design.

Original languageEnglish (US)
Pages (from-to)853-863
Number of pages11
JournalHaematologica
Volume88
Issue number8
StatePublished - Aug 1 2003
Externally publishedYes

Keywords

  • CML
  • PS-341
  • STI571-resistant cell lines

ASJC Scopus subject areas

  • Hematology

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    Gatto, S., Scappini, B., Pham, L., Onida, F., Milella, M., Ball, G., Ricci, C., Divoky, V., Verstovsek, S., Kantarjian, H. M., Keating, M. J., Cortes, J. E., & Beran, M. (2003). The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate. Haematologica, 88(8), 853-863.