Targeted efflux transporter inhibitors - A solution to improve poor cellular accumulation of anti-cancer agents

International Journal of Pharmaceutics
Johanna HuttunenKristiina M Huttunen

Abstract

Efflux transporters function as vacuum cleaners of xenobiotics and therefore they hinder drugs to reach their targets at effective enough concentrations. Efflux pump inhibitors can be used to improve the cell accumulation of drugs, however all the current inhibitors lack selectivity towards cancer cells. l-Type amino acid transporter 1 (LAT1), which is expressed in many types of cancer cells can be utilized to target inhibitors of efflux transporters to these cells by converting the inhibitors into LAT1-utilizing prodrugs. In this study, we prepared 5 LAT1-utilizing prodrugs of an efflux pump inhibitor, probenecid (PRB). All novel compounds were transported into human breast cancer cells (MCF-7) mainly via LAT1. The compounds also interacted with either multiresistant proteins (MRPs), P-glycoprotein (P-gp) or breast cancer resistant protein (BCRP) and increased significantly (3-4-fold) the cellular accumulation of anti-cancer agent vinblastine (VBL). Consequently, this improved the anti-proliferative efficacy of VBL by decreasing the cell growth after 72 h from 100% (VBL treatment alone) to 48-75% (combination treatment). However, the same phenomenon was not seen with other chemotherapeutic, methotrexate (MTX). Therefore, the c...Continue Reading

Citations

May 7, 2020·Asian Journal of Pharmaceutical Sciences·Mariafrancesca ScaliseCesare Indiveri
Aug 9, 2021·International Journal of Biological Macromolecules·Xu ChengRupei Tang

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