Abstract

The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette (ABC) transporters P-gp (P-glycoprotein, ABCB1), multidrug resistance-associated protein 1, ABCC1 and breast cancer resistance protein, ABCG2 (BCRP). These transporters are constitutively expressed in many tissues playing relevant protective roles by the regulation of the permeability of biological membranes, but they are also overexpressed in malignant tissues. P-gp is the first efflux transporter discovered to be involved in cancer drug resistance, and over the years, inhibitors of this pump have been disclosed to administer them in combination with chemotherapeutic agents. Three generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate that coadministration of pump inhibitors elicits an improvement in therapeutic efficacy of antitumor agents, although some of the latest compounds show better results. Therefore, new and innovative strategies, such as the fallback to natural products and the discover of dual activity ligands emerged as new perspectives. BCRP is the most recently ABC protein identified to be involved in multidrug resistance. It is overexpressed in several haematological and solid tumours together with P-gp, threatening the therapeutic effectiveness of different chemotherapeutic drugs. The chemistry of recently described BCRP inhibitors and dual P-gp/BCRP inhibitors, as well as their preliminary pharmacological evaluation are discussed, and the most recent advances concerning these kinds of MDR modulators are reviewed.

Highlights

  • The resistance of cancer cells to antineoplastic agents represents a substantial limitation to effective chemotherapy

  • An intriguing aspect that emerged from the studies was that the ATP-binding cassette (ABC) transporters P-gp, MRPs and BCRP are often co-expressed in tumors and that they have an overlapped specificity for a variety of substrates[103]

  • This phenomenon is often related to the overexpression of membrane proteins belonging to the ABC protein family, such as P-gp (ABCB1), BCRP (ABCG2) and MRP1 (ABCC1), which behave as efflux transporters

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Summary

Introduction

The resistance of cancer cells to antineoplastic agents represents a substantial limitation to effective chemotherapy. Analyzing the structure-activity relationships, the presence of 3,4-dimethoxy groups on ring B of the chalcone was the most efficient pattern among those investigated on MDCK II BCRP cell line, and the replacement of the amide function with an ester decreased inhibitory effects toward BCRP.

Results
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