Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells.
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 irreve...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0040853&type=printable |
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| author | Daniel B Lipka Marie-Christine Wagner Marek Dziadosz Tina Schnöder Florian Heidel Mirle Schemionek Junia V Melo Thomas Kindler Carsten Müller-Tidow Steffen Koschmieder Thomas Fischer |
| author_facet | Daniel B Lipka Marie-Christine Wagner Marek Dziadosz Tina Schnöder Florian Heidel Mirle Schemionek Junia V Melo Thomas Kindler Carsten Müller-Tidow Steffen Koschmieder Thomas Fischer |
| author_sort | Daniel B Lipka |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-797e76c3d7354db18c29dbd8b13b1d55 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-797e76c3d7354db18c29dbd8b13b1d552025-08-20T03:25:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4085310.1371/journal.pone.0040853Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells.Daniel B LipkaMarie-Christine WagnerMarek DziadoszTina SchnöderFlorian HeidelMirle SchemionekJunia V MeloThomas KindlerCarsten Müller-TidowSteffen KoschmiederThomas FischerClinical 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0040853&type=printable |
| spellingShingle | Daniel B Lipka Marie-Christine Wagner Marek Dziadosz Tina Schnöder Florian Heidel Mirle Schemionek Junia V Melo Thomas Kindler Carsten Müller-Tidow Steffen Koschmieder Thomas Fischer Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. PLoS ONE |
| title | Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. |
| title_full | Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. |
| title_fullStr | Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. |
| title_full_unstemmed | Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. |
| title_short | Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. |
| title_sort | intracellular retention of abl kinase inhibitors determines commitment to apoptosis in cml cells |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0040853&type=printable |
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