Interactions of cyclin-dependent kinase inhibitors AT-7519, flavopiridol and SNS-032 with ABCB1, ABCG2 and ABCC1 transporters and their potential to overcome multidrug resistance in vitro
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- ATP-Binding Cassette Transporters metabolism MeSH
- Madin Darby Canine Kidney Cells MeSH
- Flavonoids pharmacology MeSH
- Protein Kinase Inhibitors pharmacology MeSH
- Drug Interactions MeSH
- Humans MeSH
- Drug Resistance, Multiple MeSH
- Oxazoles pharmacology MeSH
- Piperidines pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Dogs MeSH
- Pyrazoles pharmacology MeSH
- Thiazoles pharmacology 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-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide MeSH Browser
- ATP-Binding Cassette Transporters MeSH
- alvocidib MeSH Browser
- Flavonoids MeSH
- Protein Kinase Inhibitors MeSH
- N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide MeSH Browser
- Oxazoles MeSH
- Piperidines MeSH
- Pyrazoles MeSH
- Thiazoles MeSH
PURPOSE: ATP-binding cassette (ABC) transporters play an important role in multidrug resistance (MDR) toward anticancer drugs. Here, we evaluated interactions of cyclin-dependent kinase inhibitors (CDKi) AT-7519, flavopiridol and SNS-032 with the following ABC transporters in vitro: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated protein 1 (ABCC1). METHODS: Inhibitory potency of studied CDKi to the transporters was evaluated by accumulation assays using fluorescent substrates and MDCKII cells overexpressing human ABCB1, ABCG2 or ABCC1. Resistance of transporter-expressing cells to the CDKi was evaluated by XTT proliferation assay. Observed interactions of CDKi were verified by ATPase assay in ABC transporter-expressing Sf9 membrane vesicles. Combination index analysis was additionally performed in ABC transporter-expressing cancer cell lines, HepG2 and T47D. RESULTS: Flavopiridol showed a significant inhibitory potency toward ABCG2 and ABCC1. SNS-032 also decreased ABCG2-mediated efflux, while AT-7519 failed to inhibit ABCB1, ABCG2 or ABCC1. Both flavopiridol and SNS-032 showed synergistic antiproliferative effects in combination with relevant ABC transporter substrates such as daunorubicin and topotecan in cancer cells. ABCB1 was found to confer significant resistance to AT-7519 and SNS-032, but not to flavopiridol. In contrast, ABCG2 and ABCC1 conferred resistance to flavopiridol, but not to AT-7519 and SNS-032. CONCLUSION: Our data provide detailed information on interactions of flavopiridol, SNS-032 and AT-7519 with ABC transporters, which may help elucidate the pharmacokinetic behavior and toxicity of these compounds. Moreover, we show the ability of flavopiridol and SNS-032, but not AT-7519, to overcome ABC transporter-mediated MDR.
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