Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

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.

The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

“…Therefore, it is very important to profile the interaction of various nanomaterials with ABC drug transporters to maximize their positive role. The development of new compounds that aim to modulate the function of ABC proteins is a work in progress [35,36]. New compounds that interact with ABC drug transporters could still induce adverse effects.…”

“…However, the first (e.g., Verapamil, Cyclosporin, Tamoxifen, Calmodulin) and second (e.g., Dexverapamil, Valspodar, Biricodar) generation of inhibitors were not successful in trials due to nonspecificity, the need of high concentrations that lead to toxicity, alteration of the pharmacokinetics of cytotoxic drugs due to drug-drug interactions in co-administration and formulation problems (e.g., solubility, biocompatibility, stability) [14,18]. The third (e.g., Laniquidar, Elacridar, Tariquidar) and fourth generation (e.g., Neochamaejasmin B, Curcumin) of modulators are promising candidates since they show less influence in pharmacokinetics and less toxicity [35,36].…”

“…There are a lot of strategies that can be explored to achieve the aforementioned objectives. Stimuli-response nanomedicines use the tumor microenvironmental features to trigger a specific response such as releasing the nanosystems cargo (e.g., siRNA, chemotherapy agents) when there is a variation in pH [44] or redox state of the cell [45], or in the presence of overexpressed enzymes [36]. These stimuli change the structure of the nanoparticle facilitating the release of the cargo.…”

Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer

“…Quercetin has been shown to enhance the therapeutic outcome of cisplatin in a synergistic fashion, and sensitivity of breast cancer cell lines to Dox [ 54 , 55 ]. In addition to showing cytotoxicity, quercetin and similar chromones have been identified as modulators of P-gp, MRP-1, and BCRP [ 20 , 56 , 57 ]. It is important to note that conversion of the hydroxyl in these natural products to the corresponding methyl ethers improved the inhibitory activity towards MDR efflux pumps.…”

“…P-gp, which is also referred to as MDR protein-1 (MDR1 or ABCB1) is the most studied ABC transporter and associated with MDR [ 12 , 18 , 19 ]. Two other ABC transporters responsible for MDR in cancer cells are MDR-associated protein 1 (MRP1 or ABCC1) and breast cancer resistance protein (BCRP or ABCG2) [ 12 , 20 , 21 ]. P-gp is a dimeric membrane glycoprotein, and the two halves exhibit about 43% sequence homology.…”