Drug resistance of cancer cells is crucially affected by expression levels of ABC-transporters
| Autor: | Eliska Ruzickova, Petr Mlejnek, Petr Dolezel |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine transporter expression level Abcg2 ABCG2 Dasatinib ATP-binding cassette transporter Drug resistance 03 medical and health sciences 0302 clinical medicine Medicine lcsh:QH301-705.5 drug resistance biology business.industry ABCB1 transporter expression 030104 developmental biology lcsh:Biology (General) 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research General Agricultural and Biological Sciences business medicine.drug |
| Zdroj: | BioDiscovery, Vol 20, Iss, Pp 1-13 (2017) BioDiscovery 20: e11211 |
| ISSN: | 2050-2966 |
| DOI: | 10.3897/biodiscovery.20.e11211 |
| Popis: | Dasatinib (DAS), a second generation of tyrosine kinase inhibitor (TKI), represents excellent choice for the treatment of chronic myeloid leukemia resistant to imatinib. Unfortunately, recent laboratory studies suggested that antiproliferative effect of DAS might be significantly reduced due to the overexpression of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2. However, whether these drug transporters might compromise therapeutic effect of DAS in clinic is unclear. We believe that the drug transporter expression level is a crucial factor that affects the results and its consideration may help to explain the existing controversy. In addition, clinically relevant concentrations of drug must be used. In our study, human leukemia K562 cells with high and low expression levels of ABCB1 or ABCG2 were used. DAS was applied at nanomolar concentrations. We observed that K562 cells expressing high levels of ABCB1 and ABCG2 contained significantly reduced intracellular levels of DAS and these cells exhibited significantly increased resistance to this drug. Importantly, cells with the low expression of ABCB1 or ABCG2 effluxed DAS less efficiently, however, still significantly. Accordingly, the observed resistance was lower but significant. Conclusions: The antiproliferative effects of DAS might be reduced by ABCB1 or ABCG2. However, the actual effect of these ABC transporters on DAS efficiency depends on their expression levels. The lower expression levels of ABC transporters mediate lower resistance. Considering the fact that expression levels of ABCB1 and ABCG2 transporters are usually low in clinical samples, their contribution to the overall resistance to DAS is probably low but significant. |
| Databáze: | OpenAIRE |
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