(Section A: Molecular, Structural, and Cellular Biology of Drug Transporters) The MRP-Related and BCRP / ABCG2 Multidrug Resistance Proteins: Biology, Substrate Specificity and Regulation

Haimeur, Anass; Conseil, Gwenaëlle; Deeley, Roger G.; Cole, Susan P.C.

doi:10.2174/1389200043489199

Cited by 458 publications

(393 citation statements)

References 0 publications

Supporting

Mentioning

377

Contrasting

Unclassified

Order By: Relevance

“…Normally, the presence of efflux transporters in the BBB prevents drugs and toxins from accumulating in the brain. However, their efflux activity restricts the entry of specific drugs, including those used for HAART, into the CNS and contributes to the phenomenon that the brain is intrinsically resistant to treatment with several cytotoxic and antiviral drugs (Haimeur et al, 2004), including those used for HAART. Current guidelines for HAART recommend the combination of at least three agents from at least two different therapeutic classes.…”

Section: Discussionmentioning

confidence: 99%

HIV-TAT Protein Upregulates Expression of Multidrug Resistance Protein 1 in the Blood–Brain Barrier

Hayashi

Peng

András

et al. 2005

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Central nervous system (CNS) complications of human immunodeficiency virus (HIV) infection remain a serious health risk in HIV/acquired immunodeficiency syndrome despite significant advances in highly active antiretroviral therapy (HAART). Specific drugs used for HAART are substrates for the efflux transport systems, such as the multidrug resistance-associated proteins (MRPs), which are present on brain microvascular endothelial cells (BMEC) and astrocytes, that is, the main cell types that form the blood-brain barrier (BBB). Thus, drugs employed in HAART are actively removed from the CNS and do not efficiently inhibit HIV replication in the brain. To study the potential mechanisms of this process, the aim of the present research was to address the hypothesis that HIV Tat protein can contribute to upregulation of MRP expression at the BBB level. Tat is a protein produced and released by HIV-infected cells, which may play an important role in brain vascular pathology in the course of HIV infection. Among the family of MRPs, exposure to Tat specifically induced MRP1 messenger ribonucleic acid and protein expression both in BMEC and astrocytes. These alterations were accompanied by enhanced MRP1-mediated efflux functions. Furthermore, activation of the mitogen-activated protein kinase signaling cascade was identified as the mechanism involved in Tat-mediated overexpression of MRP1. These results indicate that Tat exposure can lead to alterations of the BBB functions and decrease HAART efficacy in the CNS through overexpression of drug efflux transporters.

show abstract

Section: Discussionmentioning

confidence: 99%

HIV-TAT Protein Upregulates Expression of Multidrug Resistance Protein 1 in the Blood–Brain Barrier

Hayashi

Peng

András

et al. 2005

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…This protein is abundantly expressed in liver and kidney cell membranes, and to a lesser extent in tissues affected by PXE, including skin, retina and vessel walls (Kool et al, 1999;Bergen et al, 2000). MRP6 belongs to a family of transmembrane proteins which function as efflux transporters (Dean et al, 2001;Haimeur et al, 2004). The physiological function of MRP6 is still unknown, but recent reports suggest its implication in transmembrane transport of glutathionated metabolites (Belinsky et al, 2002;Ilias et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

et al. 2006

View full text Add to dashboard Cite

Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G>T. In the ABCC6 promoter we found the polymorphisms c.-127C>T, c.-132C>T, and c.-219A>C. The difference in the c.-219A>C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A>C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.

show abstract

“…Some members of this superfamily function to eliminate endogenous and xenobiotic metabolites, and over 12 ABC transporters have been linked to MDR. Importantly, there is a substantial overlap in the list of substrates for ABCB1, ABCG2 and the various ABCC family members linked with MDR, in spite of significant differences in the primary sequences of these transporters (Haimeur et al, 2004). This phenomenon makes treatment of multidrug-resistant cancer unsuccessful despite the various chemotherapeutic drugs that are available.…”

mentioning

confidence: 99%

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno

Fostel²,

et al. 2008

Br J Cancer

111

View full text Add to dashboard Cite

Understanding the mechanisms of multidrug resistance (MDR) could improve clinical drug efficacy. Multidrug resistance is associated with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clinically relevant drug concentrations are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concentrations reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 nM doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference analysis confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter association, indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines.

show abstract

(Section A: Molecular, Structural, and Cellular Biology of Drug Transporters) The MRP-Related and BCRP / ABCG2 Multidrug Resistance Proteins: Biology, Substrate Specificity and Regulation

Cited by 458 publications

References 0 publications

HIV-TAT Protein Upregulates Expression of Multidrug Resistance Protein 1 in the Blood–Brain Barrier

HIV-TAT Protein Upregulates Expression of Multidrug Resistance Protein 1 in the Blood–Brain Barrier

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Contact Info

Product

Resources

About