Multidrug resistance associated proteins in multidrug resistance

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Abstract

Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters. These ABC transporters together form the largest branch of proteins within the human body. The MRP family comprises of 13 members, of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell. They are mainly lipophilic anionic transporters and are reported to transport free or conjugates of glutathione (GSH), glucuronate, or sulphate. In addition, MRP1 to MRP3 can transport neutral organic drugs in free form in the presence of free GSH. Collectively, MRPs can transport drugs that differ structurally and mechanistically, including natural anticancer drugs, nucleoside analogs, antimetabolites, and tyrosine kinase inhibitors. Many of these MRPs transport physiologically important anions such as leukotriene C4, bilirubin glucuronide, and cyclic nucleotides. This review focuses mainly on the physiological functions, cellular resistance characteristics, and probable in vivo role of MRP1 to MRP9.

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Most cited references 179

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Structure and mechanism of ABC transporter proteins.

Roger Dawson, Christopher Locher, Kaspar Hollenstein (2007)

ATP-binding cassette (ABC) transporters are ubiquitous membrane proteins that couple the transport of diverse substrates across cellular membranes to the hydrolysis of ATP. The crystal structures of four ABC transporters have recently been determined. They reveal similar arrangements of the conserved ATP-hydrolyzing nucleotide-binding domains, but unrelated architectures of the transmembrane domains, with the notable exception of a common 'coupling helix' that is essential for transmitting conformational changes. The structures suggest a mechanism that rationalizes ATP-driven transport: While binding of ATP appears to trigger an outward-facing conformation, dissociation of the hydrolysis products may promote an inward-facing conformation. This basic scheme can, in principle, explain nutrient import by ABC importers and drug extrusion by ABC exporters.

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Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates.

Michael Dean, Tarmo Annilo (2004)

The ATP-binding cassette (ABC) superfamily of genes encode membrane proteins that transport a diverse set of substrates across membranes. Mutations in ABC transporters cause or contribute to many different Mendelian and complex disorders including adrenoleukodystrophy, cystic fibrosis, retinal degeneration, hypercholesterolemia, and cholestasis. The genes play important roles in protecting organisms from xenobiotics and transport compounds across the intestine, blood-brain barrier, and the placenta. There are 48 ABC genes in the human genome divided into seven subfamilies based on amino acid sequence similarities and phylogeny. These seven subfamilies are represented in all eukaryotic genomes and are therefore of ancient origin. Sequencing the genomes of numerous vertebrate organisms has allowed the complement of ABC transporters to be characterized and the evolution of the genes to be assessed. Most ABC transporters are conserved in all vertebrates, but there are also several examples of recent duplication and gene loss. For genes with a conserved ortholog, animal models have been identified or developed that can be used to probe the function and regulation of selected genes. Genes that are restricted to a specific group of animals may represent specialized functions that could provide insight into unique biological properties of that organism. Further characterization of all ABC transporters from the human genome and from model organisms will lead to additional insights into normal physiology and human disease.

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Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.

Radhika G. Bhardwaj, Daryl Kurz, Lesley Stewart … (1992)

The doxorubicin-selected lung cancer cell line H69AR is resistant to many chemotherapeutic agents. However, like most tumor samples from individuals with this disease, it does not overexpress P-glycoprotein, a transmembrane transport protein that is dependent on adenosine triphosphate (ATP) and is associated with multidrug resistance. Complementary DNA (cDNA) clones corresponding to messenger RNAs (mRNAs) overexpressed in H69AR cells were isolated. One cDNA hybridized to an mRNA of 7.8 to 8.2 kilobases that was 100- to 200-fold more expressed in H69AR cells relative to drug-sensitive parental H69 cells. Overexpression was associated with amplification of the cognate gene located on chromosome 16 at band p13.1. Reversion to drug sensitivity was associated with loss of gene amplification and a marked decrease in mRNA expression. The mRNA encodes a member of the ATP-binding cassette transmembrane transporter superfamily.

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Author and article information

Journal

Journal ID (nlm-ta): Chin J Cancer

Journal ID (iso-abbrev): Chin J Cancer

Journal ID (publisher-id): CJC

Title: Chinese Journal of Cancer

Publisher: Sun Yat-sen University Cancer Center

ISSN (Print): 1000-467X

ISSN (Electronic): 1944-446X

Publication date (Print): February 2012

Volume: 31

Issue: 2

Pages: 58-72

Affiliations

[1]Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.

Author notes

Corresponding Author: Zhe-Sheng Chen, Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA. Tel: +1-718-990-1432; Fax: +1-718-990-1877; Email: chenz@ 123456stjohns.edu .

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Publisher ID: cjc-31-02-058

DOI: 10.5732/cjc.011.10329

PMC ID: 3777468

PubMed ID: 22098952

SO-VID: 6c291b43-a42d-4592-bb87-1c3b5c919032

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.

Multidrug resistance associated proteins in multidrug resistance

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Abstract

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Karger: Oncology

Most cited references 179

Structure and mechanism of ABC transporter proteins.

Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates.

Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.

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