No correlation between the proliferative status of Bcr-Abl positive cell lines and the proapoptotic activity of imatinib mesylate (Gleevec™/Glivec®)

Paul La Rosée, Lei Shen, Eric P. Stoffregen, Michael Deininger, Brian Druker

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Imatinib mesylate (Gleevec™, formerly STI571) has been shown to be a safe and effective treatment for chronic myelogenous leukemia (CML). However, despite high rates of hematologic and cytogenetic remissions, molecular remissions are rare. Recent work has revealed the existence of a population of Bcr-Abl-positive, quiescent hematopoietic CML stem cells that are insensitive to induction of apoptosis by imatinib ex vivo. Thus, quiescence is postulated as a mechanism of molecular resistance to imatinib. To model a cell population with reduced cell cycle activity in vitro, we applied three different established approaches to block the cell cycle at the G1/S boundary using Bcr-Abl-positive cell lines. Subsequently, the cells were exposed to imatinib and apoptosis after 48 h of treatment was determined by analysis of activated caspase-3 and apoptotic DNA strand breaks. In these models, reduced cell cycle activity did not have a significant impact on the ability of imatinib to induce apoptosis. These data suggest that the proapoptotic activity of imatinib in vitro is not dependent on cell cycle transit. We conclude that resistance of primary CML cells that are insensitive to imatinib may be the result of molecular properties causing drug resistance rather than a consequence of quiescence itself.

Original languageEnglish (US)
Pages (from-to)413-419
Number of pages7
JournalHematology Journal
Volume4
Issue number6
DOIs
StatePublished - 2003

Fingerprint

Cell Line
Cell Cycle
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Apoptosis
Imatinib Mesylate
DNA Breaks
Drug Resistance
Cytogenetics
Caspase 3
Population
Stem Cells
In Vitro Techniques

Keywords

  • Apoptosis
  • Bcr-Abl
  • Cell cycle
  • Imatinib mesylate
  • Quiescene
  • Resistance

ASJC Scopus subject areas

  • Hematology

Cite this

No correlation between the proliferative status of Bcr-Abl positive cell lines and the proapoptotic activity of imatinib mesylate (Gleevec™/Glivec®). / La Rosée, Paul; Shen, Lei; Stoffregen, Eric P.; Deininger, Michael; Druker, Brian.

In: Hematology Journal, Vol. 4, No. 6, 2003, p. 413-419.

Research output: Contribution to journalArticle

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