Abstract
Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Academic Editor: Qiao-Hong ChenReceived: 8 October 2020Accepted: 17 December 2020Published: 22 December 2020Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.license.Cancer is an ongoing burden for humanity with increasing costs for therapy of patients [1,2,3]
multidrug resistance (MDR) is the main problem in anticancer treatment, especially in the case of metastatic cancer that generally cannot be treated as it would afford the effectiveness of various anticancer drugs
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Specific targeting drugs have been developed which address tumor-specific structures [4] They cause fewer side effects but have a limited use only for special kinds of cancer in single cases [4]. Transmembrane efflux pumps are known as causative agents in most cases of MDR [11,13] They pump anticancer drugs that were taken up by the cancer cells out of the cells so that the cell becomes resistant toward the treatment with the used drug [13]. The use of protein kinase inhibitors in co-application with anticancer drugs showed a benefit due to such modulation of a transmembrane efflux pump activity [11,22,23]. Substituent-dependent effects on the activity were found, and one of the best compounds was evaluated to resensitize the resistant cell line toward the cytostatic drug 6-mercaptopurine as a proof of principle
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