title: In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture.
abstract: Failure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P-glycoprotein (P-gp). P-gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P-gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P-gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P-gp inhibitors for use as co-therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716-726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug-like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P-gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P-gp-mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naïve prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 μmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P-gp inhibition are excellent leads for the development of co-therapeutics for the treatment of multidrug resistances.
authors.affiliation: Department of Biological Sciences, The Center for Drug Discovery, Design and Delivery, Southern Methodist University Dallas, Texas, 75275-0376.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Follit
authors.affiliation: Department of Biological Sciences, The Center for Drug Discovery, Design and Delivery, Southern Methodist University Dallas, Texas, 75275-0376.
authors.forename: Frances K
authors.initials: FK
authors.lastname: Brewer
authors.affiliation: Department of Biological Sciences, The Center for Drug Discovery, Design and Delivery, Southern Methodist University Dallas, Texas, 75275-0376.
authors.forename: John G
authors.initials: JG
authors.lastname: Wise
authors.affiliation: Department of Biological Sciences, The Center for Drug Discovery, Design and Delivery, Southern Methodist University Dallas, Texas, 75275-0376.
authors.forename: Pia D
authors.initials: PD
authors.lastname: Vogel
keywords: In silico drug screens; MDR inhibitors; P-glycoprotein; multidrug resistance; reversing drug resistance