Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Abstract

One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents-multidrug resistance (MDR). As P-glycoprotein (P-gp) is one of the most studied ATP-dependent efflux pumps that are frequently involved in drug efflux from cancer cells, the development of MDR modulators with the ability to inhibit P-gp efflux is considered a promising approach for overcoming MDR. However, the development of P-gp modulators have been hampered due to the absence of knowledge on the intrinsic molecular aspects by which efflux occurs, namely the specific steps that correlates drug recognition, ATP binding and efflux-related conformational changes. Experimental evidences for these processes are also difficult to obtain and only provide small pieces of information that need to be assembled for better comprehension of a wider and complex process that is drug efflux. A promising alternative relies on cutting-edge computational techniques to provide new insights on key aspects that are determinant to understand how P-gp efflux can be effectively reversed. With the contribution of ligand-based or structure-based computational methods, P-gp drug efflux is slowly becoming a dynamic and reactive process rather than a simple response to drug binding, with the complex architecture of ABC transporters playing a determinant role not only in drug recognition but in the coordination of ATP-driven conformational changes that ultimately drives drug efflux. The major enlightenments that computational studies provided toward a better comprehension of MDR and P-gp efflux phenomena are hereby described.The demographic effect of this pathology on the general population, especially in the industrialized countries, is becoming severely affected by a rapid increase in the number of new cancers (Figure 1). It is estimated that by 2030 the number of new cases (excluding nonmelanoma skin cancer) will grow 32.8% (more than 21 million), with an estimated increase of 34.6% (1.3 million) in the total number of deaths. 2,3 Thus, new and improved chemotherapy regimens are needed to counterweight such predictions. However, cancer therapy evolution is directly related to a greater knowledge on the basic molecular mechanisms Volume 5, January/February 2015 Although the above structures contributed to a better comprehension of the ABC exporters' topology, a Volume 5, January/February 2015

Do adsorbed drugs onto P-glycoprotein influence its efflux capability?

“…Substrates and modulators seem to induce a more efficient TMD reorientation/repacking, which can be due to the previously reported interaction with the ICHs at the TMD-NBD interface and enhanced communication between both domains. As already suggested in a previous paper, 38 these data support the hypothesis that targeting the TMD-NBD interface with small molecules able to decouple TMD-NBD motions would affect the coordinated NBD-TMD motions the same way as mutations in the ICH do. [109][110][111] Membrane biophysics.…”

“…Moreover, and taking into account that P-gp is a polyspecific efflux pump, the estimation of the drug adsorption free energy towards the transporter and membrane or changes in normal motion patterns may become new suitable molecular descriptors to characterize the efflux susceptibility of molecules commonly described as nonsubstrates, substrates and modulators. 38 As stated above, MD studies are increasingly contributing to the knowledge on efflux mechanism by ABC transporters. 38 Computational studies have been used to estimate the interactions and adsorption free energies of peptides 32,39,40 or small molecules 41,42 with several surfaces or lipid bilayers.…”

“…38 As stated above, MD studies are increasingly contributing to the knowledge on efflux mechanism by ABC transporters. 38 Computational studies have been used to estimate the interactions and adsorption free energies of peptides 32,39,40 or small molecules 41,42 with several surfaces or lipid bilayers. 43,44 This technique was also successfully used to evaluate cooperative adsorptions at the vacuum-water interface.…”

Homology modelling of human P-glycoprotein

“…In recent years, there has been substantial progress in using structural and computational methods to improve our understanding of multi-drug efflux mechanisms [1,2]. However, by far the most studied is P-glycoprotein (P-gp).…”

Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer

“…Overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) is one of the main and best understood causes of MDR [8, 9]. ABC transporters act as drug efflux pumps, which can dramatically extrude many antitumor drugs from the target cancer cells, and then reduce the intracellular drug concentration, so limiting the anticancer effect of the drug in tumors.…”