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Lysosomal Sequestration Determines Intracellular Imatinib Levels.

Herman Burger1, Alexander T den Dekker1, Sandra Segeletz1

  • 1Department of Medical Oncology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands (H.B., A.T.D., S.Se., A.W.M.B., P.B., S.Sl., R.H.J.M., E.A.C.W.); Department of Human Genetics, Catholic University Leuven and University Hospitals, Leuven, Belgium (M.D.-R.); Division of Human Health and Medical Science, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi, Japan (T.T.); and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.).

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Summary

Intracellular imatinib levels are primarily determined by lysosomal sequestration, not the SLC22A1 transporter. This finding impacts understanding imatinib drug accumulation and efficacy in cancer cells.

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Area of Science:

  • Pharmacology
  • Cell Biology
  • Oncology

Background:

  • The influx transporter SLC22A1 (organic cation transporter 1) is thought to control imatinib's intracellular uptake and retention (IUR).
  • Alternative mechanisms governing intracellular imatinib levels remain largely unexplored.

Purpose of the Study:

  • To systematically investigate alternative mechanisms of imatinib IUR.
  • To determine the role of SLC22A1 and other transporters in imatinib IUR.
  • To evaluate the functional consequences of imatinib sequestration.

Main Methods:

  • Quantitative uptake determination using liquid chromatography-tandem mass spectrometry.
  • Subcellular localization by fluorescent microscopy and LysoTracker Red costaining.
  • Functional assays including immunoblotting, cell cycle analysis, and apoptosis assays.

Main Results:

  • High intracellular imatinib concentrations were observed in various cell lines (HEK293, K562, SD-1, GIST-T1).
  • Imatinib IUR was time-, dose-, temperature-, and energy-dependent, independent of SLC22A1.
  • Lysosomal sequestration was confirmed as the primary mechanism for imatinib retention, with inhibitors decreasing IUR.
  • Inhibition of lysosomal sequestration increased apoptosis in GIST-T1 cells but did not affect c-Kit signaling or cell cycle arrest.

Conclusions:

  • Intracellular imatinib levels are primarily determined by lysosomal sequestration.
  • SLC22A1 expression does not substantially contribute to imatinib IUR.
  • Lysosomal sequestration influences imatinib-induced apoptosis in sensitive cells.