Breast cancer resistance protein (BCRP/MXR/ABCG2) in adult acute lymphoblastic leukaemia: frequent expression and possible correlation with shorter disease‐free survival

Suvannasankha, Attaya; Minderman, Hans; O’Loughlin, Kieran L.; Nakanishi, Takeo; Ford, Laurie; Greco, William R.; Wetzler, Meir; Ross, Douglas D.; Baer, Maria R.

doi:10.1111/j.1365-2141.2004.05211.x

Cited by 56 publications

(44 citation statements)

References 20 publications

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“…This was similar to previous reports in which BCRP RNA was more highly expressed in 30% of acute leukemia patients (Suvannasankha et al, 2004). Several SNPs were associated with higher BCRP hepatic expression.…”

Section: Discussionsupporting

confidence: 81%

Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms

Balasubramanian¹,

Lamba²,

Strom³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The hypothesis was tested that sequence diversity in breast cancer resistance protein (BCRP)'s cis-regulatory region is a significant determinant of BCRP expression. The BCRP promoter and intron 1 were resequenced in lymphoblast DNA from the polymorphism discovery resource (PDR) 44 subset. BCRP single nucleotide polymorphisms (SNPs) were genotyped in donor human livers, intestines, and lymphoblasts quantitatively phenotyped for BCRP mRNA expression. Carriers of the ؊15622C>T SNP had lower BCRP expression in multiple tissues. The intron 1 SNP 16702C>T was associated with high expression in livers; 1143G>A was associated with low expression in intestine; 12283T>C was associated with higher expression in the PDR44 and White livers. The ؊15994C>T promoter SNP was significantly associated with higher BCRP expression in multiple tissues. Patients with the ؊15994C>T genotype had substantially higher clearance of p.o. imatinib. We next determined whether BCRP expression was related to polymorphic alternative splicing or alternative promoter use. Liver polymorphically expressed an alternatively spliced mRNA [splice variant (SV) 1] skipping exon 2. Although SV1؉ livers did not uniformly carry the exon 2 G34A allele, 90% of G34A livers expressed SV1 (versus 4% of 34GG livers). BCRP mRNA was significantly lower among Hispanic livers with the G34A variant genotype and may be due, in part, to polymorphic exon 2 splicing. Analysis of allele expression imbalance (AEI) showed that PDR44 samples with AEI had lower BCRP mRNA expression; however, no linked cis-polymorphisms were identified. BCRP used multiple promoters, and livers differentially using alternative exon 1b had lower BCRP. In conclusion, BCRP expression in lymphoblasts, liver, and intestine is associated with novel promoter and intron 1 SNPs.

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Section: Discussionsupporting

confidence: 81%

Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms

Balasubramanian¹,

Lamba²,

Strom³

et al. 2008

Drug Metab Dispos

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“…There was no measurable change in HEK-293 R482 cells, which had very low uptake, much less than the pcDNA control. Although immunologically detected ABCG2 does not always correlate with functional activity (25), it is likely that high transport activity in HEK-293 R482 cell limits the amount of photosensitizer accumulation and the amount available for efflux.…”

Section: Resultsmentioning

confidence: 99%

“…The amount of HPPH transport was not directly proportional to the expression of ABCG2 measured by Western blot analysis, as exemplified by BCC-1 cells, which had higher levels of ABCG2 expression but exhibited a lesser degree of HPPH transport than the other cell lines with ABCG2 expression. Discordance between expression and function of ABCG2 has been previously shown in cancer cells (25). RIF-1 is commonly used in preclinical models for PDT.…”

Section: Discussionmentioning

confidence: 99%

The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2

Liu¹,

Baer

Bowman³

et al. 2007

Clinical Cancer Research

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131

134

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Purpose: The ATP-binding cassette protein ABCG2 (breast cancer resistance protein) effluxes some of the photosensitizers used in photodynamic therapy (PDT) and, thus, may confer resistance to this treatment modality. Tyrosine kinase inhibitors (TKI) can block the function of ABCG2. Therefore, we tested the effects of the TKI imatinib mesylate (Gleevec) on photosensitizer accumulation and in vitro and in vivo PDTefficacy. Experimental Design: Energy-dependent photosensitizer efflux and imatinib mesylate's effects on intracellular accumulation of clinically used second-and first-generation photosensitizers were studied by flow cytometry in murine and human cells with and without ABCG2 expression. Effects of ABCG2 inhibition on PDT were examined in vitro using cell viability assays and in vivo measuring photosensitizer accumulation and time to regrowth in a RIF-1tumor model. Results: Energy-dependent efflux of 2-(1-hexyloxethyl)-2-devinyl pyropheophorbide-a (HPPH, Photochlor), endogenous protoporphyrin IX (PpIX) synthesized from 5-aminolevulenic acid, and the benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin) was shown in ABCG2+ cell lines, but the first-generation multimeric photosensitizer porfimer sodium (Photofrin) and a novel derivative of HPPH conjugated to galactose were minimally transported. Imatinib mesylate increased accumulation of HPPH, PpIX, and BPD-MA from 1.3-to 6-fold in ABCG2+ cells, but not in ABCG2À cells, and enhanced PDTefficacy both in vitro and in vivo. Conclusions: Second-generation clinical photosensitizers are transported out of cells by ABCG2, and this effect can be abrogated by coadministration of imatinib mesylate. By increasing intracellular photosensitizer levels in ABCG2+ tumors, imatinib mesylate or other ABCG2 transport inhibitors may enhance efficacy and selectivity of clinical PDT.Photodynamic therapy (PDT) is used for the treatment of many cancers. Photosensitizers are taken up by tumor cells and then activated by light (1), generating reactive oxygen species that cause cell death by necrosis or apoptosis (2). Expression of ATP-binding cassette (ABC) transport proteins renders tumor cells resistant to chemotherapy drugs that are substrates of these proteins (3), and the effect of these transporters on intracellular photosensitizer accumulation has been examined as a potential cause of resistance to PDT. The ABC family transport protein that has been most thoroughly investigated is ABCB1, or P-glycoprotein, but photosensitizers were found not to be substrates for this pump (4 -8), nor were they substrates for ABCC1, or multidrug resistance-associated protein-1 (8). In contrast, another ABC family transport protein, ABCG2 or breast cancer resistance protein, has been found to transport some photosensitizers and to decrease intracellular photosensitizer accumulation (8). Jonker et al. (9) showed that ABCG2 knock-out mice were photosensitive because of increased protoporphyrin IX (PpIX) levels. Robey et al. found that pheophorbide a is a specific substrate for...

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“…In acute lymphoblastic leukemia (ALL), ABCG2 expression was more abundant in B-cell lineage ALL, with a function to produce significant drug resistance (275). More and more data indicate that individuals with higher ABCG2 expression in their leukemic blast cells have a higher probability of poor response to chemotherapy (28,354,358,378).…”

Section: Abcg2 Expression In Tumorsmentioning

confidence: 99%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

643

532

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In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the “chemoimmunity” network, which has a number of features reminiscent of classical immunology.

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Breast cancer resistance protein (BCRP/MXR/ABCG2) in adult acute lymphoblastic leukaemia: frequent expression and possible correlation with shorter disease‐free survival

Cited by 56 publications

References 20 publications

Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms

Association of Breast Cancer Resistance Protein/ABCG2 Phenotypes and Novel Promoter and Intron 1 Single Nucleotide Polymorphisms

The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

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