Targeting MDR in breast and lung cancer: Discriminating its potential importance from the failure of drug resistance reversal studies

Abstract

This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies.

Rewired Metabolism in Drug-resistant Leukemia Cells

“…Consequently, under therapeutic pressure, following the principles of natural selection, cancer cell populations that are most adaptive or resistant to treatment will be selected for, resulting in relapsing disease often associated with a worse prognosis (1,4,5). Relapse is commonly accompanied by overexpression of the ATP-binding cassette transporter ABCB1 gene product, P-glycoprotein (P-gp) 3 (multidrug resistance protein 1) (6), a drug efflux pump that is a marker for both tumor resistance to chemotherapy and a more aggressive phenotype (7)(8)(9). However, P-gp inhibition has been unsuccessful in clinical trials (7,8) so it is imperative to identify other targetable molecular mechanisms that are essential for cells with a drug-resistant phenotype to improve the prognosis of relapsing leukemia.…”

Cytotoxic Effects and Multidrug Resistance Modulation by Five Benzophenones and a Xanthone Isolated fromHypericum AnnulatumMoris SUBSP.Annulatum

“…one of the major hurdles limiting the usefulness of antineoplastic chemotherapy is the emergence of acquired resistance against anticancer agents in tumors that have been initially treatment-responsive (2). Such drug resistance phenomena could be very specific to a certain agent or a class of pharmacologically similar drugs, on the one hand, or could be non-specific, denoted as multidrug resistance (MDR), on the other (11).…”

“…Different classes of MDR modulators (either specific for P-gp or broad spectrum ABC-transporter inhibitors) have been identified and some of these have been subject to clinical trials (2,13,21,39,41,53,56). Among the chemically diverse P-gp modulators there are many natural products or their derivatives (13,19,26,32,42).…”

“…the ABcsuperfamily of membrane efflux transporters is distinguished by a well-preserved homology of AtP binding domains, and there are forty-eight ABC genes identified in humans (15,16,18,32,51,52). nevertheless, besides P-gp, only few other AtPefflux pumps have been established to confer MDR-phenotype in tumor cells, namely the multidrug resistance associated proteins (MRP), such as MRP-1 (ABcc1), MRP3 (ABcc3), MRP4 (ABcc4) (2,4,9,13,43,48,56), and the breast cancer resistance proteins (BcRP; mitoxantrone resistance proteins, MXR) (15).…”

“…one of the possible methods for overcoming resistance is to administer anticancer drugs concomitantly with non-cytotoxic substances called chemosensitizers or MDR-modulators, capable of inhibiting ABc transporters, and hence restoring the chemosensitivity of malignant cells (2,14,15,19,21,26,28,30,32,46,50).…”