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)

Abstract

Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by cross‐resistance of cells against chemotherapeutic agents, which are used for treatment of e.g., cancer, bacterial infections, or human immunodeficiency virus (HIV) infections. One group of proteins that combines all three stated aspects—the metabolism and distribution of drugs as well as their own regulation—is adenosine triphosphate‐binding cassette (ABC) transporters. These efflux pumps use the energy of adenosine triphosphate hydrolysis for drug translocation from the membrane and the cytosol to the extracellular space, often with cotransport of a cosubstrate. Multidrug resistance‐associated protein 1 (MRP1, ABCC1) had been discovered as one major key player in cancer‐related MDR. The xenobiotic substrates include anthracyclines, vinca alkaloids, podophyllotoxins, as well as glutathione (GSH)‐adducts of certain cytostatics. Contrary to other transport proteins involved in cancer‐related MDR the activity of MRP1 is related to the GSH content of cells. A modern strategy to overcome MRP1‐associated MDR is besides its inhibition the activation of GSH efflux, enforcing cell death due to cellular stress. In addition, it has recently been found that MRP1 contributes to the β‐amyloid protein clearance in Alzheimer's disease (AD). Collectively, transport activation of MRP1 is of therapeutic value, and furthermore helps to elucidate the transport protein function and the mechanisms behind it. This review is meant to summarize the known concepts of MRP1 activation, which might contribute to a further understanding of MRP1 in particular and ABC transporters in general.

Vesicular ATP-binding cassette transporters in human disease: relevant aspects of their organization for future drug development

“…Technically, multitarget modulation of ABC transporters has until now only been described for inhibitors [54][55][56][57], which potentially qualifies them for application in cancer-related MDR [1]. However, in AD, these inhibitors may serve as template structures for ABC transporter activation as a potential treatment option against AD development and/or progression, since certain compound classes were shown to comprise of both inhibitors and activators [58,59]. Hence, considering all data available on (multitarget) modulators of ABC transporters [1], analysis of the biological data and its correlation to functional substructures of the respective molecule(s), as well as identification of molecular components as indicators for broad-spectrum interaction [53], novel nonselective (promiscuous) activators might be found.…”

“…Awareness of the target and its localization is key for future drug development, which applies to cancer-related MDR, AD and other diseases with ABC transporter participation (e.g., atherosclerosis). Within the last 40 years, a comprehensive knowledge regarding ABC transporters, their basic functional aspects, as well as interfering small molecules has accumulated [59,66]. However, we still have a limited understanding of ABC transporters, their functional roles, localization sites and specific involvement in disease development and progression.…”

Abcc1 and Ggt5 support lymphocyte guidance through export and catabolism of S -geranylgeranyl- l -glutathione

“…We now add GGG as another endogenous substrate of ABCC1. ABCC1 transporter activity is not known to be regulated or gated beyond its ATP requirement (12,25). Instead, the expression pattern of the transporter is likely to be a key determinant of where GGG export occurs.…”

Multidrug Resistance in Hepatocellular Carcinoma

“…Extensive studies have been carried out during the last few decades to enhance the efficacy of chemotherapy by suppressing or evading the mechanisms of MDR. These approaches include the use of MDR modulators or chemosensitizers (79,80), improved drug delivery (81,82), RNAi therapy (83), and natural products (84).…”