The Functions and Structure of ABC Transporters: Implications for the Design of New Inhibitors of Pgp and MRP1 to Control Multidrug Resistance (MDR)

Abstract

Multidrug resistance (MDR) is a kind of acquired resistance of microorganisms and cancer cells to chemotherapic drugs that are characterized by different chemical structure and different mechanism of action. Classic MDR is the consequence of the over-expression of a variety of proteins that extrude the chemotherapic from the cell, lowering its concentration below the effective one. The ABC (ATP Binding Cassette) is a ubiquitous and important family of such transporter proteins. Members of this super family are present in mammals as well as in prokaryotic organisms and use ATP as the energy source to activate the extrusion process. P-glycoprotein (Pgp) and Multidrug Resistance Proteins (MRP1 and sister proteins) are the most important and widely studied members of ABC super family.Our knowledge about the structures and functions of transporter proteins has definitely improved in recent years, following the resolution of the structure of bacterial pumps which opened the way to the building of homology models for the more complex Pgp and MRP. It can be anticipated that these results will have a strong impact on the design of more potent and safer MDR reverters.A huge number of small molecules, many of natural origin, are able to reverse multidrug resistance by inhibiting the functions of Pgp, MRP1 and sister proteins and their action has been considered a possible way to reverse MDR. However, while a few compounds have reached clinical trials, none of them has, so far, been cleared for therapeutic use. Two main reasons are at the base of this difficulty: i) MDR is a complex phenomenon that may arise from several different biochemical mechanisms, with the consequence that inhibition of transporter proteins may be insufficient to reverse it; ii) the physiological role of Pgp and sister proteins requires more potent modulators with proper selectivity and pharmacokinetic in order to avoid unwanted side effects. This paper first reviews the most recent discoveries on the structures and functions of the ABC super family, in particular Pgp and MRP. Then, the medicinal chemistry of MDR reverters, in light of these findings, is discussed and the molecules that are presently in development are reviewed.

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…These ABC transporters participate in diverse cellular processes, including drug resistance and metabolism, transport of lipids and organic anions, and iron metabolism [54,55]. The various transporters exhibit different catalytical properties (for instance substrate specificity, mode of transport, transporter vs channel, protein-protein interactions), and additional substances that are transported by the ABC molecules include peptides, amino acids, carbohydrates, vitamins, glucoronide, glutathione conjugates and xenobiotics [59][60][61][62][63]. In eukaryotes, the ABC transporters are located in the plasma membrane and the membranes of intracellular compartments such as the Golgi, endosomes and in the mitochondria [61].…”

“…It is a membrane-associated 663 amino-acid transporter that is highly expressed in placenta and HSCs (SP/CD34 ) [71][72][73]. ABCG2 exhibits transporter [64,59,75,76]. For instance, the human ABC transporter subfamily C (symbol ABCC) consists of 12 members, nine of which comprise a group of multidrug resistance proteins (also known as MRP1-MRP9 or ABCC1-ABCC6, ABCC10-ABCC12) [64,65,76,77].…”

Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating P‐glycoprotein activity and PI3K/Akt pathway

“…1 Human Pgp (MDR1) and its rodent homologues mdr-1 and mdr-3 are conserved proteins that translocate antitumor agents across the plasma membrane of resistant cancer cells, reducing intracellular drug concentrations to sublethal levels. 2 Pgp-mediated drug efflux can be modulated by MDR inhibitors, which block transport in a competitive or noncompetitive way. Although many Pgp inhibitors (including verapamil, cyclosporin A and PSC833) are able to sensitize drug-resistant cell lines to antitumor agents in vitro, they have not always been useful in clinical trails since they appear to be either toxic or ineffective in vivo.…”

Reversal of the multidrug resistance of human ileocecal adenocarcinoma cells by acetyl-11-keto-β-boswellic acid <i>via</i> downregulation of P-glycoprotein signals

“…P-glycoprotein (P-gp) is encoded by multidrug resistance gene 1 (MDR1) and is a member of the ATPbinding cassette (ABC) superfamily (2). High levels of P-gp expression have been linked to the efflux of chemotherapeutic drugs in cancer cells.…”