Conference 2021 Live Talk
Screening of FDA approved drugs as modulators of Multidrug Resistance Protein 2 (MRP2/ABCC2) protein expression in MRP2-overexpressing cells
Authors and Affiliations
Vivian Osei Poku1, Surtaj Iram1
1. Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota, USA
Multidrug Resistance Protein 2 (MRP2/ABCC2) is a member of the ATP-binding cassette superfamily of transporters, and serves as an ATP-dependent unidirectional efflux pump. It is highly expressed in the liver where it governs the elimination of bilirubin glucuronides into the bile, as such mutations in MRP2 is reported to be associated with the Dubin Johnson’s Syndrome (DJS). MRP2 is also involved in renal elimination in the kidneys, and distribution of its substrates in the placenta and the gastrointestinal tract. It is a major player in the transport of numerous clinically important compounds across multiple drug classes including antibiotics, antihypertensive and anticancer agents, and Its overexpression has been implicated in the development of multidrug resistance (MDR) of tumor cells including hepatocellular, ovarian, breast, lung and colorectal carcinomas. The MRP2 transporter is of great clinical importance, and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drug targets. Here, we screened for modulators of MRP2 using a high throughput cell-based functional assay.
A unique FDA drug library (372 drugs) was screened using a high throughput In-cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. MRP2-overexpressing MDCKII (MDCKII/MRP2) cells were treated with drug concentration of 10uM for 48 hours . Treatments were performed in triplicates, and experiments were done using the 96 – well format. Data obtained was statistically analyzed using Microsoft Excel and Graph Pad Prism version 6.0. Drugs that showed modulation above 50% were considered as Hits. Future works would focus on characterization of these hit compounds to determine their concentration and time dependent effect on MRP2 protein levels and their impact on MRP2 efflux activity.
Initial screening from our study revealed 49 hit compounds that changed the MRP2 expression levels by more than 50% representing 13.17% of total compounds screened. Of which, 10.48% increased expression levels whereas 2.69% lowered expression levels of MRP2 after drug treatment.
Our findings from this initial screening showed that modulators of MRP2 peregrinates multiple drug families, and signifies the importance of profiling drug interactions with this transporter.