6533b7d5fe1ef96bd1265167

RESEARCH PRODUCT

Identification of new P-glycoprotein inhibitors derived from cardiotonic steroids

Brigitte KoppErnst UrbanThomas EfferthMalte PaulsenMaen ZeinoMartin Zehl

subject

Cell SurvivalHigh-throughput screeningIn silicoPharmacologyBiochemistryProtein Structure SecondaryCell LineFlow cytometryCardiac Glycosideschemistry.chemical_compoundmedicineHumansATP Binding Cassette Transporter Subfamily B Member 1P-glycoproteinPharmacologyDose-Response Relationship Drugbiologymedicine.diagnostic_testResazurinmedicine.diseaseIn vitroProtein Structure TertiaryLeukemiachemistryDoxorubicinCancer cellbiology.protein

description

P-glycoprotein (ABCB1, MDR1) is capable of extruding chemotherapeutics outside the cell and its overexpression in certain cancer cells may cause failure of chemotherapy. Many attempts were carried out to identify potent inhibitors of this transporter and numerous compounds were shown to exert inhibitory effects in vitro, but so far none were able to make their way to the clinic due to serious complications. Natural compounds represent a great source of therapeutics, which are believed to be safe and effective. Therefore, we have screened a large library of naturally occurring cardiotonic steroids and their derivatives using high throughput flow cytometry. We were able to identify six compounds capable of modulating P-glycoprotein activity. By using P-glycoprotein ATPase assays, molecular docking in silico studies and resazurin reduction assays, the outcome of this high throughput screening platform has been validated. These novel compounds may serve as candidates to reverse doxorubicin resistance in leukemia cells.

yearjournalcountryeditionlanguage
2014-07-28Biochemical Pharmacology
https://doi.org/10.1016/j.bcp.2014.10.009