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| ChemMedChem. 2017 Apr 23. doi: 10.1002/cmdc.201700225 |
| Synthesis and SAR Study of Anticancer Protoflavone Derivatives: Investigation of Cytotoxicity and Interaction with ABCB1 and ABCG2 Multidrug Efflux Transporters. |
| Dankó B1, Tóth S2, Martins A3, Vágvölgyi M4, Kúsz N5, Molnár J6, Chang FR7, Wu YC8, Szakács G9, Hunyadi A10 |
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Abstract There is a constant need for new therapies against multidrug-resistant (MDR) cancer. Natural compounds are a promising source of novel anticancer agents. We recently showed that protoflavones display activity in MDR cancer cell lines that overexpress the P-glycoprotein (P-gp) drug efflux pump. In this study, 52 protoflavones, including 22 new derivatives, were synthesized and tested against a panel of drug-sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics. With the exception of protoapigenone, identified as a weak ABCG2 substrate, all protoflavones bypass resistance conferred by these two transporters. The majority of the compounds were found to exhibit mild to strong (up to 13-fold) selectivity against the MCF-7Dox and KB-V1 cell lines, but not to transfected MDR cells engineered to overexpress the MDR transporters. Our results suggest that protoflavones can overcome MDR cancer by evading P-gp-mediated efflux. |
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. |
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KEYWORDS: MDR cancer, P-glycoprotein, collateral sensitivity, cross-resistance, protoflavones |
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Publikations ID: 28436164 Quelle: öffnen |
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