Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

Abstract

Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high-throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1-mediated MDR, from the time of its discovery until today. The focus lies on small-molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1-overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1-related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1-mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad-spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

“…In contrast to their MRP1‐blocking behavior, certain flavonoids (apigenin, fisetin, galangin, luteolin, myricein, and rhoifolin) decreased intracellular daunorubicin concentration at 100 µM to 62.3%, 59.6%, 67.9%, 65.3%, 76.8%, and 58.2% of control, respectively, after 2 hours of exposure . The same applied with respect to vinblastine accumulation [fisetin (53.6%), myricetin (87.7%), naringenin (89.5%), and rutin (71.8%)].…”

“…137 Finally, the GSH analog DNP-SG activated the ATPase of MRP1 in GLC 4 /ADR-derived membrane vesicles at 10 µM about 23%. 155 The leukotriene D 4 (LTD 4 ) antagonist MK571 (verlukast), one of the most widely used standard MRP1 inhibitors, 29 was shown by Wu et al 148 to moderately stimulate the MRP1 ATPase at low concentrations (up to 20 µM), and inhibiting the ATPase at higher concentrations (50-100 µM). 148 Inhibition by MK571 (5-100 µM) was also observed when the ATPase was a priori stimulated with quercetin (10 µM).…”

“…The main focus of ABC transporter research within the last 40 years laid mostly on the search/finding and improvement/development of inhibitors to treat MDR‐conferring cancer cells . Here again, the first discoveries concerned P‐gp, as this was the very first described ABC transporter involved in the MDR phenotype .…”

“…Recently, we have summarized the knowledge which has accumulated within the last four decades regarding inhibition of MRP1 and related processes . Since a fund of inhibitors was already known regarding P‐gp, most of these compound were tested against MRP1—which was discovered one and a half decades later—leading to the very first MRP1 inhibitors such as verapamil and cyclosporine A .…”

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

“…The fact that some pesticides are highly lipophilic compounds interacting with lipid membranes can also be involved . For MRP1 and MRP2, which act as glutathione‐conjugate transporters, a reduction of intracellular glutathione level can participate in the inhibition of their activities, as well as the alteration of the intracellular trafficking of these pumps …”