Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1 and ABCG2 and an inhibitor of human ABCC1 in vitro
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26300056
DOI
10.1016/j.bcp.2015.08.099
PII: S0006-2952(15)00544-4
Knihovny.cz E-resources
- Keywords
- ABCB1, ABCC1, ABCG2, Cytotoxicity, Dinaciclib, Dinaciclib (PubChem CID: 46926350), Multidrug resistance,
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ATP-Binding Cassette Transporters metabolism MeSH
- Adenosine Triphosphatases metabolism MeSH
- Bridged Bicyclo Compounds, Heterocyclic metabolism pharmacology MeSH
- Biological Transport MeSH
- Madin Darby Canine Kidney Cells MeSH
- Cyclic N-Oxides MeSH
- Cyclin-Dependent Kinases antagonists & inhibitors MeSH
- Indolizines MeSH
- Protein Kinase Inhibitors metabolism pharmacology MeSH
- Humans MeSH
- Neoplasm Proteins metabolism MeSH
- ATP Binding Cassette Transporter, Subfamily B metabolism MeSH
- Multidrug Resistance-Associated Proteins metabolism MeSH
- Dogs MeSH
- Pyridinium Compounds metabolism pharmacology MeSH
- In Vitro Techniques 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
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ATP-Binding Cassette Transporters MeSH
- ABCB1 protein, human MeSH Browser
- ABCG2 protein, human MeSH Browser
- Adenosine Triphosphatases MeSH
- Bridged Bicyclo Compounds, Heterocyclic MeSH
- Cyclic N-Oxides MeSH
- Cyclin-Dependent Kinases MeSH
- dinaciclib MeSH Browser
- Indolizines MeSH
- Protein Kinase Inhibitors MeSH
- multidrug resistance-associated protein 1 MeSH Browser
- Neoplasm Proteins MeSH
- ATP Binding Cassette Transporter, Subfamily B MeSH
- Multidrug Resistance-Associated Proteins MeSH
- Pyridinium Compounds MeSH
Dinaciclib is a novel cyclin-dependent kinase inhibitor (CDKI) with significant activity against various cancers in vitro and in vivo. ABC efflux transporters play an important role in drug disposition and are responsible for multidrug resistance in cancer cells. Inhibitors and substrates of these transporters may participate in pharmacokinetic drug-drug interactions (DDIs) that alter drug disposition during pharmacotherapy. To assess such risks associated with dinaciclib we evaluated its possible effects on efflux activities of ABCB1, ABCC1 and ABCG2 transporters in vitro. Monolayer transport, XTT cell proliferation, ATPase and intracellular accumulation assays were employed. Here, we show that the transport ratio of dinaciclib was far higher across monolayers of MDCKII-ABCB1 and MDCKII-ABCG2 cells than across MDCKII parental cell layers, demonstrating that dinaciclib is a substrate of ABCB1 and ABCG2. In addition, overexpression of ABCB1, ABCG2 and ABCC1 conferred resistance to dinaciclib in MDCKII cells. In ATPase assays, dinaciclib decreased stimulated ATPase activity of ABCB1, ABCG2 and ABCC1, confirming it has interactive potential toward all three transporters. Moreover, dinaciclib significantly inhibited ABCC1-mediated efflux of daunorubicin (EC50=18 μM). The inhibition of ABCC1 further led to a synergistic effect of dinaciclib in both MDCKII-ABCC1 and human cancer T47D cells, when applied in combination with anticancer drugs. Taken together, our results suggest that ABC transporters can substantially affect dinaciclib transport across cellular membranes, leading to DDIs. The DDIs of dinaciclib with ABCC1 substrate chemotherapeutics might be exploited in novel cancer therapies.
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