title: Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells.
abstract: Clinical development of imatinib in CML established continuous target inhibition as a paradigm for successful tyrosine kinase inhibitor (TKI) therapy. However, recent reports suggested that transient potent target inhibition of BCR-ABL by high-dose TKI (HD-TKI) pulse-exposure is sufficient to irreversibly commit cells to apoptosis. Here, we report a novel mechanism of prolonged intracellular TKI activity upon HD-TKI pulse-exposure (imatinib, dasatinib) in BCR-ABL-positive cells. Comprehensive mechanistic exploration revealed dramatic intracellular accumulation of TKIs which closely correlated with induction of apoptosis. Cells were rescued from apoptosis upon HD-TKI pulse either by repetitive drug wash-out or by overexpression of ABC-family drug transporters. Inhibition of ABCB1 restored sensitivity to HD-TKI pulse-exposure. Thus, our data provide evidence that intracellular drug retention crucially determines biological activity of imatinib and dasatinib. These studies may refine our current thinking on critical requirements of TKI dose and duration of target inhibition for biological activity of TKIs.
authors: Department of Hematology and Oncology, University Medical Center, Otto-von-Guericke-University, Magdeburg, Germany.
authors: Daniel B
authors: DB
authors: Lipka
authors: Marie-Christine
authors: MC
authors: Wagner
authors: Marek
authors: M
authors: Dziadosz
authors: Tina
authors: T
authors: Schnöder
authors: Florian
authors: F
authors: Heidel
authors: Mirle
authors: M
authors: Schemionek
authors: Junia V
authors: JV
authors: Melo
authors: Thomas
authors: T
authors: Kindler
authors: Carsten
authors: C
authors: Müller-Tidow
authors: Steffen
authors: S
authors: Koschmieder
authors: Thomas
authors: T
authors: Fischer
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000068877:Imatinib Mesylate; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D018528:ATP-Binding Cassette Transporters; D017304:Annexin A5; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D053148:Caspase 3