scispace - formally typeset
Search or ask a question
Journal ArticleDOI

P-glycoprotein: from genomics to mechanism

20 Oct 2003-Oncogene (Nature Publishing Group)-Vol. 22, Iss: 47, pp 7468-7485
TL;DR: A model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell is proposed, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported.
Abstract: Resistance to chemically different natural product anti-cancer drugs (multidrug resistance, or MDR) results from decreased drug accumulation, resulting from expression of one or more ATP-dependent efflux pumps. The first of these to be identified was P-glycoprotein (P-gp), the product of the human MDR1 gene, localized to chromosome 7q21. P-gp is a member of the large ATP-binding cassette (ABC) family of proteins. Although its crystallographic 3-D structure is yet to be determined, sequence analysis and comparison to other ABC family members suggest a structure consisting of two transmembrane (TM) domains, each with six TM segments, and two nucleotide-binding domains. In the epithelial cells of the gastrointestinal tract, liver, and kidney, and capillaries of the brain, testes, and ovaries, P-gp acts as a barrier to the uptake of xenobiotics, and promotes their excretion in the bile and urine. Polymorphisms in the MDR1 gene may affect the pharmacokinetics of many commonly used drugs, including anticancer drugs. Substrate recognition of many different drugs occurs within the TM domains in multiple-overlapping binding sites. We have proposed a model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported. Understanding of the biology, genetics, and biochemistry of P-gp promises to improve the treatment of cancer and explain the pharmacokinetics of many commonly used drugs.
Citations
More filters
Journal ArticleDOI
TL;DR: Highly dynamic mitotic-spindle microtubules are among the most successful targets for anticancer therapy, and it is now known that at lower concentrations, microtubule-targeted drugs can suppress micro Tubule dynamics without changingmicrotubule mass; this action leads to mitotic block and apoptosis.
Abstract: Highly dynamic mitotic-spindle microtubules are among the most successful targets for anticancer therapy. Microtubule-targeted drugs, including paclitaxel and Vinca alkaloids, were previously considered to work primarily by increasing or decreasing the cellular microtubule mass. Although these effects might have a role in their chemotherapeutic actions, we now know that at lower concentrations, microtubule-targeted drugs can suppress microtubule dynamics without changing microtubule mass; this action leads to mitotic block and apoptosis. In addition to the expanding array of chemically diverse antimitotic agents, some microtubule-targeted drugs can act as vascular-targeting agents, rapidly depolymerizing microtubules of newly formed vasculature to shut down the blood supply to tumours.

4,007 citations

Journal ArticleDOI
26 Jan 2007-Science
TL;DR: It is hypothesized that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.
Abstract: Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.

2,480 citations

Journal ArticleDOI
TL;DR: This review discusses the current knowledge on the molecular mechanisms involved in both types of resistance in bacteria.
Abstract: Large amounts of antibiotics used for human therapy, as well as for farm animals and even for fish in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. Multidrug resistance in bacteria may be generated by one of two mechanisms. First, these bacteria may accumulate multiple genes, each coding for resistance to a single drug, within a single cell. This accumulation occurs typically on resistance (R) plasmids. Second, multidrug resistance may also occur by the increased expression of genes that code for multidrug efflux pumps, extruding a wide range of drugs. This review discusses our current knowledge on the molecular mechanisms involved in both types of resistance.

1,331 citations

Journal ArticleDOI
TL;DR: An important goal is to develop quantitative models that detail the kinetic and molecular mechanisms by which ABC transporters couple the binding and hydrolysis of ATP to substrate translocation.
Abstract: ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of integral membrane proteins that are responsible for the ATP-powered translocation of many substrates across membranes. The highly conserved ABC domains of ABC transporters provide the nucleotide-dependent engine that drives transport. By contrast, the transmembrane domains that create the translocation pathway are more variable. Recent structural advances with prokaryotic ABC transporters have provided a qualitative molecular framework for deciphering the transport cycle. An important goal is to develop quantitative models that detail the kinetic and molecular mechanisms by which ABC transporters couple the binding and hydrolysis of ATP to substrate translocation.

1,087 citations

Journal ArticleDOI
TL;DR: Evidence is presented indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood–brain barrier, and push forward their clinical application as biomarkers and as targets in combination therapies in order to improve anticancer drug efficiency.
Abstract: Most patients who die of cancer have disseminated disease that has become resistant to multiple therapeutic modalities. Ample evidence suggests that the expression of ATP-binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), which is encoded by ABC subfamily B member 1 (ABCB1), can confer resistance to cytotoxic and targeted chemotherapy. However, the development of MDR1 as a therapeutic target has been unsuccessful. At the time of its discovery, appropriate tools for the characterization and clinical development of MDR1 as a therapeutic target were lacking. Thirty years after the initial cloning and characterization of MDR1 and the implication of two additional ABC transporters, the multidrug resistance-associated protein 1 (MRP1; encoded by ABCC1)), and ABCG2, in multidrug resistance, interest in investigating these transporters as therapeutic targets has waned. However, with the emergence of new data and advanced techniques, we propose to re-evaluate whether these transporters play a clinical role in multidrug resistance. With this Opinion article, we present recent evidence indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood–brain barrier.

1,033 citations

References
More filters
Journal ArticleDOI
TL;DR: The ability to predict and circumvent drug resistance is likely to improve chemotherapy, and it has become apparent that resistance exists against every effective drug, even the authors' newest agents.
Abstract: Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.

5,105 citations


"P-glycoprotein: from genomics to me..." refers background in this paper

  • ...Subsequently, other members of this family of transporters such as MRP1 (ABCC1) and MXR (ABCG2) have been shown to be capable of conferring MDR by virtue of energydependent drug efflux (reviewed in Litman et al., 2001; Borst and Elferink, 2002; Gottesman et al., 2002)....

    [...]

  • ...In addition, we have suggested that some of the ABC transporters, such as P-gp, might prove useful as selectable markers for gene therapy, or to protect bone marrow during cancer therapy (Gottesman et al., 2002)....

    [...]

  • ...Although there have been several generations of P-gp modulators in development, reversing P-gp-mediated MDR in the clinic has met with very limited success (Gottesman et al., 2002; Leonard et al., 2002)....

    [...]

Journal ArticleDOI

3,591 citations


"P-glycoprotein: from genomics to me..." refers background in this paper

  • ...Some of these agents may carry a positive charge at physiological pH, but due to their amphipathic nature they can enter cells by passive diffusion (Gottesman and Pastan, 1993)....

    [...]

Journal ArticleDOI
04 Dec 1992-Science
TL;DR: Reversion to drug sensitivity was associated with loss of gene amplification and a marked decrease in mRNA expression, and the mRNA encodes a member of the ATP-binding cassette transmembrane transporter superfamily.
Abstract: 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.

3,030 citations


"P-glycoprotein: from genomics to me..." refers background in this paper

  • ...Subsequently, MRP1 (ABC C1) was isolated from an MDR lung cancer cell line where MDR1 was not expressed (Cole et al., 1992)....

    [...]

  • ...…Glutathione and other conjugates, organic anions, leukotriene C4 Doxorubicin, epirubicin, etoposide, vincristine, methotrexate Borst et al. (2000); Cole et al. (1992); Jedlitschky et al. (1996); Loe et al. (1998); Muller et al. (1994) MRP2, cMOAT ABCC2 Liver, kidney, intestine Similar to MRP1,…...

    [...]

Journal ArticleDOI
TL;DR: A significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function is observed and this polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of M DR-1.
Abstract: To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

2,452 citations


"P-glycoprotein: from genomics to me..." refers background or result in this paper

  • ...A methodical screening for polymorphisms of the entire MDR1 gene, performed by Hoffmeyer et al. (2000) on a healthy Caucasian population, revealed 15 different SNPs in exons and introns....

    [...]

  • ...Another explanation for the same phenomenon is that the Caucasian white population was undefined or not divided into specific ethnic groups (Hoffmeyer et al., 2000), while other studies investigated narrower populations (Decleves et al., 2000; Cascorbi et al., 2001)....

    [...]

  • ...…of P-gp, and increased digoxin bioavailability; individuals carrying the CC genotype were found to have high intestinal P-gp levels and low intestinal digoxin uptake, while individuals carrying the TT genotype had low intestinal P-gp levels and high digoxin uptake (Hoffmeyer et al., 2000)....

    [...]

  • ...Another study examined 268 Caucasian men, half of whom were lung cancer patients, and found similar frequencies of genotypes to Hoffmeyer et al. (2000) (Sinues et al., 2003)....

    [...]

  • ...However, a frequency of 13.3% homozygosity for the same allele was found in Caucasians (Hoffmeyer et al., 2000)....

    [...]

Journal ArticleDOI
TL;DR: In this article, the authors identify a 2.4-kb mRNA that encodes a 663-aa member of the ATP-binding cassette superfamily of transporters that they termed breast cancer resistance protein (BCRP).
Abstract: MCF-7/AdrVp is a multidrug-resistant human breast cancer subline that displays an ATP-dependent reduction in the intracellular accumulation of anthracycline anticancer drugs in the absence of overexpression of known multidrug resistance transporters such as P glycoprotein or the multidrug resistance protein. RNA fingerprinting led to the identification of a 2.4-kb mRNA that is overexpressed in MCF-7/AdrVp cells relative to parental MCF-7 cells. The mRNA encodes a 663-aa member of the ATP-binding cassette superfamily of transporters that we term breast cancer resistance protein (BCRP). Enforced expression of the full-length BCRP cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin accumulation and retention, and causes an ATP-dependent enhancement of the efflux of rhodamine 123 in the cloned transfected cells. BCRP is a xenobiotic transporter that appears to play a major role in the multidrug resistance phenotype of MCF-7/AdrVp human breast cancer cells.

2,235 citations