Off‑target effect of imatinib and nilotinib on human vitamin D3 metabolism
| Autor: | Claudia Günther, Josephine T. Tauer, Andrea Bauer, Lysann Kroschwald, Nick Zimmermann, Meinolf Suttorp |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Calcitriol Biology Pharmacology Biochemistry Cell Line 03 medical and health sciences 0302 clinical medicine parasitic diseases Genetics medicine Humans Molecular Biology Protein Kinase Inhibitors Cholecalciferol Oncogene fungi food and beverages Imatinib Cell cycle HaCaT 030104 developmental biology Pyrimidines Oncology Nilotinib Apoptosis 030220 oncology & carcinogenesis Cancer research Imatinib Mesylate Molecular Medicine Tyrosine kinase medicine.drug |
| Zdroj: | Molecular medicine reports. 17(1) |
| ISSN: | 1791-3004 |
| Popis: | Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated in vitro, the influence of IMA and NIL on VD3 metabolism i) in HaCaT cells and ii) in cultured outer root sheath keratinocytes (ORS‑KC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL. Concomitantly, specific inhibitors were applied to analyze the inhibition of the VD3 processing cytochrome P450 isoenzyme family by TKIs. In vitro, IMA and NIL significantly impaired the production of calcitriol in HaCaT and cultured ORS‑KC cells from hair follicles of IMA treated children. For NIL, this inhibitory effect demonstrated a 4‑fold increase. In HaCaT and ORS‑KC, application of specific CYP450 inhibitors revealed that CYP27B1 was impaired by IMA and NIL leading to an intracellular accumulation of calcidiol. However, during TKI treatment, KC of IMA treated children revealed no differences in calcidiol and calcitriol levels. In conclusion, IMA and NIL interfere with the vitamin D3 cascade due to their metabolism by CYP27B1. |
| Databáze: | OpenAIRE |
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