Cyclin-dependent kinase inhibitors AZD5438 and R547 show potential for enhancing efficacy of daunorubicin-based anticancer therapy: Interaction with carbonyl-reducing enzymes and ABC transporters
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
30826329
DOI
10.1016/j.bcp.2019.02.035
PII: S0006-2952(19)30083-8
Knihovny.cz E-resources
- Keywords
- ABC transporters, Carbonyl reducing enzymes, Daunorubicin, Drug resistance,
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Daunorubicin administration & dosage adverse effects analogs & derivatives therapeutic use MeSH
- Imidazoles administration & dosage pharmacology MeSH
- Cloning, Molecular MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Neoplasm Proteins metabolism MeSH
- Heart Diseases chemically induced MeSH
- Cell Proliferation MeSH
- Multidrug Resistance-Associated Proteins metabolism MeSH
- Antineoplastic Agents administration & dosage therapeutic use MeSH
- Dogs MeSH
- Pyrimidines administration & dosage pharmacology MeSH
- Gene Expression Regulation, Enzymologic drug effects MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Dogs MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- (4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl)(2,3-difluoro-6-methoxyphenyl)methanone MeSH Browser
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ABCG2 protein, human MeSH Browser
- AZD5438 MeSH Browser
- Daunorubicin MeSH
- daunorubicinol MeSH Browser
- Imidazoles MeSH
- multidrug resistance-associated protein 1 MeSH Browser
- Neoplasm Proteins MeSH
- Multidrug Resistance-Associated Proteins MeSH
- Antineoplastic Agents MeSH
- Pyrimidines MeSH
Daunorubicin (DAUN) has served as an anticancer drug in chemotherapy regimens for decades and is still irreplaceable in treatment of acute leukemias. The therapeutic outcome of DAUN-based therapy is compromised by its cardiotoxicity and emergence of drug resistance. This phenomenon is often caused by pharmacokinetic mechanisms such as efflux of DAUN from cancer cells through ATP-binding cassette (ABC) transporters and its conversion to less cytostatic but more cardiotoxic daunorubicinol (DAUN-OL) by carbonyl reducing enzymes (CREs). Here we aimed to investigate, whether two cyclin-dependent kinase inhibitors, AZD5438 and R547, can interact with these pharmacokinetic mechanisms and reverse DAUN resistance. Using accumulation assays, we revealed AZD5438 as potent inhibitor of ABCC1 showing also weaker inhibitory effect to ABCB1 and ABCG2. Combination index analysis, however, shown that inhibition of ABCC1 does not significantly contribute to synergism between AZD5438 and DAUN in MDCKII-ABCC1 cells, suggesting predominant role of other mechanism. Using pure recombinant enzymes, we found both tested drugs to inhibit CREs with aldo-keto reductase 1C3 (AKR1C3). This interaction was further confirmed in transfected HCT-116 cells. Moreover, these cells were sensitized to DAUN by both compounds as Chou-Talalay combination index analysis showed synergism in AKR1C3 transfected HCT-116, but not in empty vector transfected control cell line. In conclusion, we propose AZD5438 and R547 as modulators of DAUN resistance that can prevent AKR1C3-mediated DAUN biotransformation to DAUN-OL. This interaction could be beneficially exploited to prevent failure of DAUN-based therapy as well as the undesirable cardiotoxic effect of DAUN-OL.
References provided by Crossref.org
Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors
