Inhibition of AKR1B10-mediated metabolism of daunorubicin as a novel off-target effect for the Bcr-Abl tyrosine kinase inhibitor dasatinib
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34339712
DOI
10.1016/j.bcp.2021.114710
PII: S0006-2952(21)00326-9
Knihovny.cz E-resources
- Keywords
- Anthracyclines, Cancer therapy, Leukaemia, Multidrug resistance, Reductase,
- MeSH
- Aldo-Keto Reductases antagonists & inhibitors chemistry metabolism MeSH
- Fusion Proteins, bcr-abl antagonists & inhibitors chemistry metabolism MeSH
- A549 Cells MeSH
- Drug Resistance, Neoplasm drug effects physiology MeSH
- Dasatinib administration & dosage MeSH
- Daunorubicin administration & dosage MeSH
- HCT116 Cells MeSH
- Protein Kinase Inhibitors administration & dosage MeSH
- Drug Delivery Systems methods MeSH
- Humans MeSH
- Antineoplastic Agents administration & dosage MeSH
- Protein Structure, Secondary MeSH
- Molecular Docking Simulation MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- AKR1B10 protein, human MeSH Browser
- Aldo-Keto Reductases MeSH
- Fusion Proteins, bcr-abl MeSH
- Dasatinib MeSH
- Daunorubicin MeSH
- Protein Kinase Inhibitors MeSH
- Antineoplastic Agents MeSH
Bcr-Abl tyrosine kinase inhibitors significantly improved Philadelphia chromosome-positive leukaemia therapy. Apart from Bcr-Abl kinase, imatinib, dasatinib, nilotinib, bosutinib and ponatinib are known to have additional off-target effects that might contribute to their antitumoural activities. In our study, we identified aldo-keto reductase 1B10 (AKR1B10) as a novel target for dasatinib. The enzyme AKR1B10 is upregulated in several cancers and influences the metabolism of chemotherapy drugs, including anthracyclines. AKR1B10 reduces anthracyclines to alcohol metabolites that show less antineoplastic properties and tend to accumulate in cardiac tissue. In our experiments, clinically achievable concentrations of dasatinib selectively inhibited AKR1B10 both in experiments with recombinant enzyme (Ki = 0.6 µM) and in a cellular model (IC50 = 0.5 µM). Subsequently, the ability of dasatinib to attenuate AKR1B10-mediated daunorubicin (Daun) resistance was determined in AKR1B10-overexpressing cells. We have demonstrated that dasatinib can synergize with Daun in human cancer cells and enhance its therapeutic effectiveness. Taken together, our results provide new information on how dasatinib may act beyond targeting Bcr-Abl kinase, which may help to design new chemotherapy regimens, including those with anthracyclines.
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