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Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells

Daniel B Lipka1, Marie-Christine Wagner, Marek Dziadosz

  • 1Department of Hematology and Oncology, University Medical Center, Otto-von-Guericke-University, Magdeburg, Germany.

Plos One
|July 21, 2012
PubMed

Insights

High-dose tyrosine kinase inhibitors (TKIs) accumulate inside cancer cells, prolonging their effect and inducing apoptosis. This intracellular drug retention, not continuous exposure, is key to TKI efficacy in treating BCR-ABL-positive cells.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Oncology

Background:

  • Continuous target inhibition was the standard for tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML).
  • Recent studies suggest transient, high-dose TKI (HD-TKI) pulse-exposure can induce apoptosis in BCR-ABL-positive cells.

Purpose of the Study:

  • To investigate the mechanism of prolonged intracellular TKI activity after HD-TKI pulse-exposure.
  • To determine the role of intracellular drug accumulation and efflux in TKI efficacy.

Main Methods:

  • Utilized BCR-ABL-positive cell models.
  • Administered pulse-exposures of imatinib and dasatinib.
  • Investigated intracellular TKI accumulation and apoptosis induction.
  • Assessed cellular response to drug washout and ABC transporter modulation.

Main Results:

  • HD-TKI pulse-exposure led to significant intracellular accumulation of TKIs.
  • Intracellular TKI accumulation strongly correlated with apoptosis induction.
  • Apoptosis was prevented by repetitive drug washout or by overexpressing ABC drug transporters.
  • Inhibiting ABCB1 restored sensitivity to HD-TKI pulse-exposure.

Conclusions:

  • Intracellular drug retention is a critical determinant of the biological activity of imatinib and dasatinib.
  • Prolonged intracellular TKI activity, rather than continuous exposure, drives apoptosis.
  • These findings may necessitate a re-evaluation of TKI dosing and duration for optimal therapeutic outcomes.

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