Multidrug resistance

The cells have several mechanisms to gain resistance by avoiding drug cytotoxicity (Fig. 1). Examples are the decreased influx or increased efflux (1), disruption of cell death mechanisms (2), activation of general detoxifying mechanisms (3), increase in DNA repair (4), and cell cycle alterations (5). Our work in this research line is devoted to the study of mechanism (1) by which the cell gains MDR by effluxing drugs.

Central in the removal of molecules out of the cells is a family of transporters named ATP binding cassette (ABC). ABC proteins are a ubiquitous super-family of membrane transporters present in all phyla with 7 sub-families (A-G) playing central roles in drug disposition, metabolism and pharmacokinetics.

Mechanism

Although multifactorial, MDR to chemotherapy regimens can be achieved by selecting phenotypes that over-express ABC transporters. As the overexpression of such transporters is frequently observed in many cancers and tumor cell lines, ABC transporters are a potential molecular target to overcome MDR.

P-glycoprotein (Pgp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1) or breast cancer resistance protein (BCRP/ABCG2) were found to be markers of overall poor chemotherapy response and prognosis in various cancers. This way, in 2012, new guidelines from FDA specify that “all investigational drugs should be evaluated in vitro to determine whether they are a potential substrate of Pgp or BCRP” and that “evaluation of investigational drugs as inhibitors for these transporters should be conducted”.

Scientific contributions

In recent years we have produced relevant contributions in understanding the dynamics of ABC transporters and how molecules interact and are recognized. We started by isolating the chemical features that confer activity to a molecule by using ligand based approaches. We obtained and published the first functional and complete model of Pgp that we used to study the dynamics of the protein, efflux properties, transmission of signals within the transporter, drug permeation, interaction and recognition, and modulation mechanisms. More recently we published a model for ABCG2 and studied lipid and drug interaction sites, and drug affinity.