The Experts below are selected from a list of 186849 Experts worldwide ranked by ideXlab platform
Andrei Seluanov - One of the best experts on this subject based on the ideXlab platform.
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High-molecular-mass hyaluronan mediates the Cancer Resistance of the naked mole rat
Nature, 2013Co-Authors: Xiao Tian, Max Myakishev-rempel, Julia Ablaeva, Christopher Hine, Zhiyong Mao, Amita Vaidya, Jorge Azpurua, Vera Gorbunova, Andrei SeluanovAbstract:The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual Resistance to Cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of Cancer. Here we identify a mechanism responsible for the naked mole rat's Cancer Resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide Cancer Resistance and longevity to this species.
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Cancer Resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Vera Gorbunova, Julia Ablaeva, Christopher Hine, Xiao Tian, Andrei V. Gudkov, Andrei SeluanovAbstract:Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and Resistance to Cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this Resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and Cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that Cancer Resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to Cancer Resistance of this subterranean mammal extremely adapted to life underground.
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hypersensitivity to contact inhibition provides a clue to Cancer Resistance of naked mole rat
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Andrei Seluanov, Christopher Hine, Zhiyong Mao, Jorge Azpurua, Marina Feigenson, Michael J Bozzella, Kenneth C Catania, Vera GorbunovaAbstract:The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary Resistance to Cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the Cancer Resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed “early contact inhibition.” Contact inhibition is a key antiCancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27Kip1. In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16Ink4a. Furthermore, we show that the roles of p16Ink4a and p27Kip1 in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16Ink4a, and regular contact inhibition is controlled by p27Kip1. We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor Resistance of the naked mole-rat.
Vera Gorbunova - One of the best experts on this subject based on the ideXlab platform.
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High-molecular-mass hyaluronan mediates the Cancer Resistance of the naked mole rat
Nature, 2013Co-Authors: Xiao Tian, Max Myakishev-rempel, Julia Ablaeva, Christopher Hine, Zhiyong Mao, Amita Vaidya, Jorge Azpurua, Vera Gorbunova, Andrei SeluanovAbstract:The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual Resistance to Cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of Cancer. Here we identify a mechanism responsible for the naked mole rat's Cancer Resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide Cancer Resistance and longevity to this species.
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Cancer Resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Vera Gorbunova, Julia Ablaeva, Christopher Hine, Xiao Tian, Andrei V. Gudkov, Andrei SeluanovAbstract:Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and Resistance to Cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this Resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and Cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that Cancer Resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to Cancer Resistance of this subterranean mammal extremely adapted to life underground.
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hypersensitivity to contact inhibition provides a clue to Cancer Resistance of naked mole rat
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Andrei Seluanov, Christopher Hine, Zhiyong Mao, Jorge Azpurua, Marina Feigenson, Michael J Bozzella, Kenneth C Catania, Vera GorbunovaAbstract:The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary Resistance to Cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the Cancer Resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed “early contact inhibition.” Contact inhibition is a key antiCancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27Kip1. In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16Ink4a. Furthermore, we show that the roles of p16Ink4a and p27Kip1 in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16Ink4a, and regular contact inhibition is controlled by p27Kip1. We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor Resistance of the naked mole-rat.
Douglas D Ross - One of the best experts on this subject based on the ideXlab platform.
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role of breast Cancer Resistance protein bcrp abcg2 in Cancer drug Resistance
Biochemical Pharmacology, 2012Co-Authors: Karthika Natarajan, Yi Xie, Maria R Baer, Douglas D RossAbstract:Since cloning of the ATP-binding cassette (ABC) family member breast Cancer Resistance protein (BCRP/ABCG2) and its characterization as a multidrug Resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many Cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural Resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many Cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent Resistance of these neoplasms and their failure to be cured.
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identification of a novel estrogen response element in the breast Cancer Resistance protein abcg2 gene
Cancer Research, 2004Co-Authors: Sitharthan Kamalakaran, Douglas D Ross, Debra A Tonetti, William T. BeckAbstract:The breast Cancer Resistance protein (BCRP) is an ATP-binding cassette half transporter that confers Resistance to antiCancer drugs such as mitoxantrone, anthracyclines, topotecan, and SN-38. Initial characterization of the BCRP promoter revealed that it is TATA-less with 5 putative Sp1 sites downstream from a putative CpG island and several AP1 sites (K. J. Bailey-Dell et al., Biochim. Biophys. Acta, 1520: 234-241, 2001). Here, we examined the sequence of the 5'-flanking region of the BCRP gene and found a putative estrogen response element (ERE). We showed that estrogen enhanced the expression of BCRP mRNA in the estrogen receptor (ER)-positive T47D:A18 cells and PA-1 cells stably expressing ERalpha. In BCRP promoter-luciferase assays, sequential deletions of the BCRP promoter showed that the region between -243 and -115 is essential for the ER effect. Mutation of the ERE found within this region attenuated the estrogen response, whereas deletion of the site completely abrogated the estrogen effect. Furthermore, electrophoretic mobility shift assays revealed specific binding of ERalpha to the BCRP promoter through the identified ERE. Taken together, we provide evidence herein for a novel ERE in the BCRP promoter.
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Multidrug Resistance mediated by the breast Cancer Resistance protein BCRP (ABCG2)
Oncogene, 2003Co-Authors: L Austin Doyle, Douglas D RossAbstract:Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant Cancer cell lines without overexpression of P-glycoprotein or multidrug Resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing Cancer drug Resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast Cancer Resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-Resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of antiCancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential ‘side population’ stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug Resistance in clinical Cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug Resistance in human Cancers.
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expression of breast Cancer Resistance protein in blast cells from patients with acute leukemia
Blood, 2000Co-Authors: Douglas D Ross, Judith E Karp, Tar T Chen, Austin L DoyleAbstract:Breast Cancer Resistance protein (BCRP) is a novel member of the adenosine triphosphate–binding cassette superfamily of transport proteins. Transfection and enforced expression of BCRP in drug-sensitive cells confer Resistance to mitoxantrone, doxorubicin, daunorubicin, and topotecan. We studied blast cells from 21 acute leukemia patients (20 acute myeloid leukemia, 1 acute lymphocytic leukemia) for the expression of BCRP mRNA using a quantitative reverse-transcription polymerase chain reaction assay. BCRP mRNA expression varied more than 1000-fold among the samples tested, with low or barely detectable expression in half of the samples. Seven samples (33%) had relatively high expression of BCRP mRNA. High expression of BCRP did not correlate strongly with high expression of P-glycoprotein, suggesting that BCRP may cause Resistance to certain antileukemic drugs in P-glycoprotein–negative cases. High expression of BCRP mRNA is sufficiently frequent in AML to warrant more extensive investigations to determine the relation of disease subtype and treatment outcome to BCRP expression and function.
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breast Cancer Resistance protein is localized at the plasma membrane in mitoxantrone and topotecan resistant cell lines
Cancer Research, 2000Co-Authors: George L. Scheffer, William S. Dalton, Douglas D Ross, Marc Maliepaard, Aclm Pijnenborg, M A Van Gastelen, A B Schroeijers, John Allen, P Van Der Valk, J H M SchellensAbstract:Tumor cells may display a multidrug resistant phenotype by overexpression of ATP-binding cassette transporters such as multidrug Resistance (MDR1) P-glycoprotein, multidrug Resistance protein 1 (MRP1), and breast Cancer Resistance protein (BCRP). The presence of BCRP has thus far been reported solely using mRNA data. In this study, we describe a BCRP-specific monoclonal antibody, BXP-34, obtained from mice, immunized with mitoxantrone-resistant, BCRP mRNA-positive MCF-7 MR human breast Cancer cells. BCRP was detected in BCRP-transfected cells and in several mitoxantrone- and topotecan-selected tumor cell sublines. Pronounced staining of the cell membranes showed that the transporter is mainly present at the plasma membrane. In a panel of human tumors, including primary tumors as well as drug-treated breast Cancer and acute myeloid leukemia samples, BCRP was low or undetectable. Extended studies will be required to analyze the possible contribution of BCRP to clinical multidrug Resistance.
Christopher Hine - One of the best experts on this subject based on the ideXlab platform.
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High-molecular-mass hyaluronan mediates the Cancer Resistance of the naked mole rat
Nature, 2013Co-Authors: Xiao Tian, Max Myakishev-rempel, Julia Ablaeva, Christopher Hine, Zhiyong Mao, Amita Vaidya, Jorge Azpurua, Vera Gorbunova, Andrei SeluanovAbstract:The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual Resistance to Cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of Cancer. Here we identify a mechanism responsible for the naked mole rat's Cancer Resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide Cancer Resistance and longevity to this species.
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Cancer Resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Vera Gorbunova, Julia Ablaeva, Christopher Hine, Xiao Tian, Andrei V. Gudkov, Andrei SeluanovAbstract:Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and Resistance to Cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this Resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7–20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and Cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that Cancer Resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to Cancer Resistance of this subterranean mammal extremely adapted to life underground.
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hypersensitivity to contact inhibition provides a clue to Cancer Resistance of naked mole rat
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Andrei Seluanov, Christopher Hine, Zhiyong Mao, Jorge Azpurua, Marina Feigenson, Michael J Bozzella, Kenneth C Catania, Vera GorbunovaAbstract:The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary Resistance to Cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the Cancer Resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed “early contact inhibition.” Contact inhibition is a key antiCancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27Kip1. In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16Ink4a. Furthermore, we show that the roles of p16Ink4a and p27Kip1 in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16Ink4a, and regular contact inhibition is controlled by p27Kip1. We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor Resistance of the naked mole-rat.
Qingcheng Mao - One of the best experts on this subject based on the ideXlab platform.
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role of the breast Cancer Resistance protein bcrp abcg2 in drug transport an update
Aaps Journal, 2015Co-Authors: Qingcheng Mao, Jashvant D UnadkatAbstract:The human breast Cancer Resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrug-resistant breast Cancer cell line where it was found to confer Resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-d-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug Resistance and drug disposition.
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structure and function of the human breast Cancer Resistance protein bcrp abcg2
Current Drug Metabolism, 2010Co-Authors: Zsolt Bikadi, Mark F Rosenberg, Qingcheng MaoAbstract:The human breast Cancer Resistance protein (BCRP/ABCG2) is the second member of the G subfamily of the large ATP-binding cassette (ABC) transporter superfamily. BCRP was initially discovered in multidrug resistant breast Cancer cell lines where it confers Resistance to chemotherapeutic agents such as mitoxantrone, topotecan and methotrexate by extruding these compounds out of the cell. BCRP is capable of transporting non-chemotherapy drugs and xenobiotiocs as well, including nitrofurantoin, prazosin, glyburide, and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine. BCRP is frequently detected at high levels in stem cells, likely providing xenobiotic protection. BCRP is also highly expressed in normal human tissues including the small intestine, liver, brain endothelium, and placenta. Therefore, BCRP has been increasingly recognized for its important role in the absorption, elimination, and tissue distribution of drugs and xenobiotics. At present, little is known about the transport mechanism of BCRP, particularly how it recognizes and transports a large number of structurally and chemically unrelated drugs and xenobiotics. Here, we review current knowledge of structure and function of this medically important ABC efflux drug transporter.
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interactions of azole antifungal agents with the human breast Cancer Resistance protein bcrp
Journal of Pharmaceutical Sciences, 2007Co-Authors: Anshul Gupta, Jashvant D Unadkat, Qingcheng MaoAbstract:Breast Cancer Resistance protein (BCRP) is an efflux transporter that plays an important role in drug disposition. The goal of this study was to investigate the interactions of azole antifungal agents, ketoconazole, itraconazole, fluconazole, and voriconazole, with BCRP. First, the effect of the azoles on BCRP efflux activity in BCRP-overexpressing HEK cells was determined by measuring intracellular pheophorbide A (PhA) fluorescence using flow cytometry. We found that keotoconazole and itraconazole significantly inhibited BCRP-mediated efflux of PhA at low microM concentrations. However, fluconazole only mildly inhibited and voriconazole did not inhibit BCRP efflux activity at concentrations up to 100 microM. The IC(50) value of ketoconazole for inhibition of BCRP-mediated PhA efflux was 15.3 +/- 6.5 microM. Ketoconazole and itraconazole also effectively reversed BCRP-mediated Resistance of HEK cells to topotecan. When direct efflux of [(3)H]ketoconazole was measured in BCRP-overexpressing HEK cells, we found that [(3)H]ketoconazole was not transported by BCRP. Consistent with this finding, BCRP did not confer Resistance to ketoconazole and itraconazole in HEK cells. Taken together, ketoconazole and itraconazole are BCRP inhibitors, but fluconazole and voriconazole are not. These results suggest that BCRP could play a significant role in the pharmacokinetic interactions of ketoconazole or itraconazole with BCRP substrate drugs.
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breast Cancer Resistance protein 1 limits fetal distribution of nitrofurantoin in the pregnant mouse
Drug Metabolism and Disposition, 2007Co-Authors: Yi Zhang, Jashvant D Unadkat, Honggang Wang, Qingcheng MaoAbstract:The efflux transporter, the breast Cancer Resistance protein (BCRP), is most abundantly expressed in the apical membrane of the placental syncytiotrophoblasts, indicating that it could play an important role in protecting the fetus by limiting xenobiotic/drug penetration across the placental barrier. In the present study, we examined whether Bcrp1, the murine homolog of human BCRP, limits fetal distribution of the model BCRP/Bcrp1 substrate, nitrofurantoin (NFT), in the pregnant mouse. NFT was administered i.v. to FVB wild-type and Bcrp1 –/– pregnant mice. The maternal plasma samples and fetuses were collected at various times (5–60 min) after drug administration. The NFT concentrations in the maternal plasma samples and homogenates of fetal tissues were determined by a high-performance liquid chromatography/UV assay. Although the maternal plasma area under the concentration-time curve (AUC) of NFT in the Bcrp1 –/– pregnant mice (97.4 ± 10.0 μg · min/ml plasma) was only slightly (but significantly) higher than that in the wild-type pregnant mice (78.4 ± 6.0 μg · min/ml plasma), the fetal AUC of NFT in the Bcrp1 –/– pregnant mice (1493.0 ± 235.3 ng · min/g of fetus) was approximately 5 times greater than that in the wild-type pregnant mice (298.6 ± 77.4 ng · min/g of fetus). These results clearly suggest that Bcrp1 significantly limits fetal distribution of NFT in the pregnant mouse, but has only a minor effect on the systemic clearance of the drug.
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Role of the breast Cancer Resistance protein (ABCG2) in drug transport
The AAPS Journal, 2005Co-Authors: Qingcheng MaoAbstract:The 72-kDa breast Cancer Resistance protein (BCRP) is the second member of the subfamily G of the human ATP binding cassette (ABC) transporter superfamily and thus also designated as ABCG2. Unlike P-glycoprotein and MRP1, which are arranged in 2 repeated halves, BCRP is a half-transporter consisting of only 1 nucleotide binding domain followed by 1 membrane-spanning domain. Current experimental evidence suggests that BCRP may function as a homodimer or homotetramer. Overexpression of BCRP is associated with high levels of Resistance to a variety of antiCancer agents, including anthracyclines, mitoxantrone, and the camptothecins, by enhancing drug efflux. BCRP expression has been detected in a large number of hematological malignancies and solid tumors, indicating that this transporter may play an important role in clinical drug Resistance of Cancers. In addition to its role to confer Resistance against chemotherapeutic agents, BCRP actively transports structurally diverse organic molecules, conjugated or unconjugated, such as estrone-3-sulfate, 17β-estradiol 17-(β-D-glucuronide), and methotrexate. BCRP is highly expressed in the placental syncytiotrophoblasts, in the apical membrane of the epithelium in the small intestine, in the liver canalicular membrane, and at the luminal surface of the endothelial cells of human brain microvessels. This strategic and substantial tissue localization indicates that BCRP also plays an important role in absorption, distribution, and elimination of drugs that are BCRP substrates. This review summarizes current knowledge of BCRP and its relevance to multidrug Resistance and drug disposition.
