Roscovitine and purvalanol A effectively reverse anthracycline resistance mediated by the activity of aldo-keto reductase 1C3 (AKR1C3): A promising therapeutic target for cancer treatment
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
30077642
DOI
10.1016/j.bcp.2018.08.001
PII: S0006-2952(18)30320-4
Knihovny.cz E-resources
- Keywords
- AKR1C3, Anthracyclines, Cyclin-dependent kinase, Drug resistance, Inhibition,
- MeSH
- Anthracyclines pharmacology MeSH
- Hep G2 Cells MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- HCT116 Cells MeSH
- Cloning, Molecular MeSH
- Humans MeSH
- Neoplasms drug therapy MeSH
- Aldo-Keto Reductase Family 1 Member C3 genetics metabolism MeSH
- Antineoplastic Agents administration & dosage pharmacology MeSH
- Purines administration & dosage chemistry pharmacology MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Roscovitine administration & dosage chemistry pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine MeSH Browser
- AKR1C3 protein, human MeSH Browser
- Anthracyclines MeSH
- Aldo-Keto Reductase Family 1 Member C3 MeSH
- Antineoplastic Agents MeSH
- Purines MeSH
- Roscovitine MeSH
Members of the short-chain dehydrogenase/reductase (SDR) and aldo-keto reductase (AKR) superfamilies mediate the reduction of anthracyclines to their less potent C-13 alcohol metabolites. This reductive metabolism has been recognized as one of the most important factors that trigger anthracycline resistance in cancer cells. In our study, two purine analogues, purvalanol A and roscovitine, were identified as effective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an enzyme that is overexpressed in many cancer types and is also a key player in tumour cell resistance to anthracyclines. Purvalanol A and roscovitine potently inhibited human recombinant AKR1C3 (Ki = 5.5 μM and 1.4 μM, respectively) and displayed similar activity in experiments with intact cells. Ligand-protein docking calculations suggested that both inhibitors occupied a part of the cofactor-binding site. Furthermore, we demonstrated that the combination of daunorubicin with purvalanol A or roscovitine exhibited a synergistic effect in AKR1C3 overexpressing cells. Based on these findings, it is possible to presume that purvalanol A and roscovitine may have the potential to enhance the therapeutic effectiveness and safety of anthracyclines via inhibition of AKR1C3.
References provided by Crossref.org
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