Overexpression of ATP-binding cassette (ABC) transporters is often linked to multidrug resistance (MDR) in cancer chemotherapies. P-glycoprotein (P-gp) is one of the best studied drug transporters associated with MDR. There are currently no approved drugs available for clinical use in cancer chemotherapies to reverse MDR by inhibiting P-glycoprotein. Using computational studies, we previously identified several compounds that inhibit P-gp by targeting its nucleotide binding domain and avoiding its drug binding domains. Several of these compounds showed successful MDR reversal when tested on a drug resistant prostate cancer cell line. Using conventional two-dimensional cell culture of MDR ovarian and prostate cancer cells and three dimensional prostate cancer microtumor spheroids, we demonstrated here that co-administration with chemotherapeutics significantly decreased cell viability and survival as well as cell motility. The P-gp inhibitors were not observed to be toxic on their own. The inhibitors increased cellular retention of chemotherapeutics and reporter compounds known to be transport substrates of P-gp. We also showed that these compounds are not transport substrates of P-gp and that two of the three inhibit P-gp, but not the closely related ABC transporter, ABCG2/BCRP. The results presented suggest that these P-gp inhibitors may be promising leads for future drug development.
Scientific reports. 2018 Jan 17*** epublish ***
Amila K Nanayakkara, Courtney A Follit, Gang Chen, Noelle S Williams, Pia D Vogel, John G Wise
The Center for Drug Discovery, Design and Delivery, the Center for Scientific Computing, Southern Methodist University, Dallas, TX, 75275-0376, USA., Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390-9038, United States., The Center for Drug Discovery, Design and Delivery, the Center for Scientific Computing, Southern Methodist University, Dallas, TX, 75275-0376, USA. ., The Center for Drug Discovery, Design and Delivery, the Center for Scientific Computing, Southern Methodist University, Dallas, TX, 75275-0376, USA. .