“Drug resistance associated membrane proteins”

Study of drug resistance began in the late 1940’s, and recognition that altered membrane transport of drug was often related to cellular drug resistance followed approximately 20 years later. Identification and isolation of specific membrane proteins that influence this altered drug transport began in the 1970’s and is a major ongoing endeavor to this day. In this article, we refer to such proteins as “drug resistance associated membrane proteins,” or “DRAMPs.” In over 40 years, dozens of books and tens of thousands of research articles have asked how drug resistance is mediated by various DRAMPs. By comparison, relatively few studies have probed the normal physiological function of these proteins. In many cases, deletion of the gene encoding a DRAMP is not lethal, showing that the function of the protein is non-essential, but in some cases (e.g., PfCRT protein involved in antimalarial drug resistance) deletion is not possible, suggesting an essential function. For some DRAMPs a clear role in specific cell biological processes has been established (e.g., Ishikawa et al., 1997; Jin et al., 2002; Baugh et al., 2012; Quazi and Molday, 2013), but in most cases we are no closer to a detailed molecular definition of the physiologic function of DRAMPs than we were when these proteins were first discovered. When they are involved in drug resistance, DRAMPs are often either mutated or overexpressed, and in some cases both. Quantitative comparison between wild type and mutant isoforms of DRAMPs, or between normal and higher levels, is often quite difficult for a variety of technical reasons, and this has probably slowed elucidation of their physiologic function. The vast majority of genetic, biochemical, biophysical, and cell biological studies with DRAMPs have emphasized their putative interactions with drugs, and dozens of review articles summarize decades of such work (e.g., Saidijam et al., 2006; Bay et al., 2008; Blair and Piddock, 2009; Damme et al., 2011). The known array of DRAMPs is now dizzying, with hundreds of proteins now organized into five families (ABC, MATE, MFS, SMR, RND), as described elsewhere (AlvarezOrtega et al., 2013). Members of each family can be found in multiple phyla, but sequence conservation across phyla is typically quite low. Individual members of these families have been implicated in anticancer, antibacterial, antifungal, and antiparasitic drug resistance phenomena. Other papers in this volume describe specific proteins in detail. Collectively, these data related to DRAMP structure and function and their roles in drug resistance are exceedingly rich, and encompass a remarkable diversity of function. It is therefore a challenge to view them as a single class of proteins, since their only common thread is participation in drug resistance phenomena, which are biologically and chemically quite diverse. To add additional complexity, there are four possible routes to cellular drug resistance: (1) catabolism of the drug, (2) mutation and/or altered expression of the drug target, (3) switching off a relevant metabolic pathway or (4) altered cellular transport of the drug. All operate simply to reduce the efficiency of interaction between the drug and its molecular target, and membrane proteins involved in drug resistance phenomena could in theory influence any of the four routes. To date, most DRAMPs studied in depth have been associated with altered drug transport phenomena that act to promote lower drug-drug target association. The most famous of these is human MDR1 protein (P-glycoprotein), which mediates decreased accumulation of anticancer drugs in tumor cells (Roepe et al., 1996; Quazi and Molday, 2013). Early on it was appreciated that altered drug transport induced by overexpression of huMDR1 could in theory be direct or indirect (Roepe et al., 1996), meaning huMDR1 could mediate direct translocation of drugs back out of the cell to reduce net accumulation, or indirectly influence accumulation of drugs through physical chemical effects, such as changes in membrane potential that would then effect passive influx of some drugs (Wadkins and Roepe, 1997). Decades later, multiple examples of both direct and indirect phenomena can be found for various examples of drug resistance mediated by DRAMPs. Another question raised early on was whether degrees of resistance or patterns of drug “cross resistance” were mediated solely by huMDR1 and other DRAMPs. In addressing this question, of note is the fact that many early models of drug resistant cells were created by incremental exposure to increasing concentrations of a single drug (Biedler and Riehm, 1970), protocols that induce a variety of “epi-phenomena” that are now known to add to drug resistance, along with DRAMPs. For example, it is now appreciated that the 100–1000’s-fold levels of drug resistance observed in early drug selected tumor cell models are clearly not due to huMDR1 overexpression alone. A crucial concept that emerged from this