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Advanced Drug Delivery Reviews (v.61, #1)
The role of human ABC transporter ABCG2 (BCRP) in pharmacotherapy
by Toshihisa Ishikawa (Theme Editor) (pp. 1-2).
The role of human ABC transporter ABCG2 (BCRP) in pharmacotherapy
by Toshihisa Ishikawa (Theme Editor) (pp. 1-2).
ABCG2: A perspective by Robert W. Robey; Kenneth K.K. To; Orsolya Polgar; Marius Dohse; Patricia Fetsch; Michael Dean; Susan E. Bates (pp. 3-13).
ABCG2, or breast cancer resistance protein (BCRP), is an ABC transporter that has been the subject of intense study since its discovery a decade ago. With high normal tissue expression in the brain endothelium, gastrointestinal tract, and placenta, ABCG2 is believed to be important in the protection from xenobiotics, regulating oral bioavailability, forming part of the blood–brain barrier, the blood–testis barrier, and the maternal–fetal barrier. Notably, ABCG2 is often expressed in stem cell populations, where it likely plays a role in xenobiotic protection. However, clues to its epigenetic regulation in various cell populations are only beginning to emerge. While ABCG2 overexpression has been demonstrated in cancer cells after in vitro drug treatment, endogenous ABCG2 expression in certain cancers is likely a reflection of the differentiated phenotype of the cell of origin and likely contributes to intrinsic drug resistance. Notably, research into the transporter's role in cancer drug resistance and its development as a therapeutic target in cancer has lagged. Substrates and inhibitors of the transporter have been described, among them chemotherapy drugs, tyrosine kinase inhibitors, antivirals, HMG-CoA reductase inhibitors, carcinogens, and flavonoids. This broad range of substrates complements the efficiency of ABCG2 as a transporter in laboratory studies and suggests that, while there are redundant mechanisms of xenobiotic protection, the protein is important in normal physiology. Indeed, emerging studies in pharmacology and toxicology assessing polymorphic variants in man, in combination with murine knockout models have confirmed its dynamic role. Work in pharmacology may eventually lead us to a greater understanding of the physiologic role of ABCG2.
Keywords: ABCG2; BCRP; Drug-resistance; ABC transporter; Chemotherapy; Pharmacology
ABCG2: A perspective by Robert W. Robey; Kenneth K.K. To; Orsolya Polgar; Marius Dohse; Patricia Fetsch; Michael Dean; Susan E. Bates (pp. 3-13).
ABCG2, or breast cancer resistance protein (BCRP), is an ABC transporter that has been the subject of intense study since its discovery a decade ago. With high normal tissue expression in the brain endothelium, gastrointestinal tract, and placenta, ABCG2 is believed to be important in the protection from xenobiotics, regulating oral bioavailability, forming part of the blood–brain barrier, the blood–testis barrier, and the maternal–fetal barrier. Notably, ABCG2 is often expressed in stem cell populations, where it likely plays a role in xenobiotic protection. However, clues to its epigenetic regulation in various cell populations are only beginning to emerge. While ABCG2 overexpression has been demonstrated in cancer cells after in vitro drug treatment, endogenous ABCG2 expression in certain cancers is likely a reflection of the differentiated phenotype of the cell of origin and likely contributes to intrinsic drug resistance. Notably, research into the transporter's role in cancer drug resistance and its development as a therapeutic target in cancer has lagged. Substrates and inhibitors of the transporter have been described, among them chemotherapy drugs, tyrosine kinase inhibitors, antivirals, HMG-CoA reductase inhibitors, carcinogens, and flavonoids. This broad range of substrates complements the efficiency of ABCG2 as a transporter in laboratory studies and suggests that, while there are redundant mechanisms of xenobiotic protection, the protein is important in normal physiology. Indeed, emerging studies in pharmacology and toxicology assessing polymorphic variants in man, in combination with murine knockout models have confirmed its dynamic role. Work in pharmacology may eventually lead us to a greater understanding of the physiologic role of ABCG2.
Keywords: ABCG2; BCRP; Drug-resistance; ABC transporter; Chemotherapy; Pharmacology
Physiological and pharmacological roles of ABCG2 (BCRP): Recent findings in Abcg2 knockout mice by Maria L.H. Vlaming; Jurjen S. Lagas; Alfred H. Schinkel (pp. 14-25).
The multidrug transporter ABCG2 (BCRP/MXR/ABCP) can actively extrude a broad range of endogenous and exogenous substrates across biological membranes. ABCG2 limits oral availability and mediates hepatobiliary and renal excretion of its substrates, and thus influences the pharmacokinetics of many drugs. Recent work, relying mainly on the use ofAbcg2 −/− mice, has revealed important contributions of ABCG2 to the blood-brain, blood-testis and blood-fetal barriers. Together, these functions indicate a primary biological role of ABCG2 in protecting the organism from a range of xenobiotics. In addition, several other physiological functions of ABCG2 have been observed, including extrusion of porphyrins and/or porphyrin conjugates from hematopoietic cells, liver and harderian gland, as well as secretion of vitamin B2 (riboflavin) and possibly other vitamins (biotin, vitamin K) into breast milk. However, the physiological significance of these processes has been difficult to establish, indicating that there is still a lot to learn about this intriguing protein.
Keywords: BCRP/Bcrp1; Blood-brain barrier; Blood-placental barrier; Blood-testis barrier; Blood-retinal barrier; Mammary gland; Vitamin transport; Harderian gland; Porphyrins; Phytoestrogens
Physiological and pharmacological roles of ABCG2 (BCRP): Recent findings in Abcg2 knockout mice by Maria L.H. Vlaming; Jurjen S. Lagas; Alfred H. Schinkel (pp. 14-25).
The multidrug transporter ABCG2 (BCRP/MXR/ABCP) can actively extrude a broad range of endogenous and exogenous substrates across biological membranes. ABCG2 limits oral availability and mediates hepatobiliary and renal excretion of its substrates, and thus influences the pharmacokinetics of many drugs. Recent work, relying mainly on the use ofAbcg2 −/− mice, has revealed important contributions of ABCG2 to the blood-brain, blood-testis and blood-fetal barriers. Together, these functions indicate a primary biological role of ABCG2 in protecting the organism from a range of xenobiotics. In addition, several other physiological functions of ABCG2 have been observed, including extrusion of porphyrins and/or porphyrin conjugates from hematopoietic cells, liver and harderian gland, as well as secretion of vitamin B2 (riboflavin) and possibly other vitamins (biotin, vitamin K) into breast milk. However, the physiological significance of these processes has been difficult to establish, indicating that there is still a lot to learn about this intriguing protein.
Keywords: BCRP/Bcrp1; Blood-brain barrier; Blood-placental barrier; Blood-testis barrier; Blood-retinal barrier; Mammary gland; Vitamin transport; Harderian gland; Porphyrins; Phytoestrogens
Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy by Kohji Noguchi; Kazuhiro Katayama; Junko Mitsuhashi; Yoshikazu Sugimoto (pp. 26-33).
The breast cancer resistance protein, BCRP/ABCG2, is a half-molecule ATP-binding cassette transporter that facilitates the efflux of various anticancer agents from the cell, including 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. The expression of BCRP can thus confer a multidrug resistance phenotype in cancer cells, and its transporter activity is involved in the in vivo efficacy of chemotherapeutic agents. Thus, the elucidation of the substrate preferences and structural relationships of BCRP is essential to understanding its in vivo functions during chemotherapeutic treatments. Single nucleotide polymorphisms (SNPs) have also been found to be key factors in determining the efficacy of chemotherapeutics, and those therapeutics that inhibit BCRP activity, such as the SNP that results in a C421A mutant, may result in unexpected side effects of the BCRP- anticancer drugs interaction even at normal dosages. In order to modulate the BCRP activity during chemotherapy, various compounds have been tested as inhibitors of this protein. Estrogenic compounds including estrone, several tamoxifen derivatives in addition to phytoestrogens and flavonoids have been shown to reverse BCRP-mediated drug resistance. Intriguingly, recently developed molecular targeted cancer drugs, such as the tyrosine kinase inhibitors imatinib mesylate, gefitinib and others, can also interact with BCRP. Since both functional SNPs and inhibitory agents of BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of its substrate drugs, BCRP activity is an important consideration in the development of molecular targeted chemotherapeutics.
Keywords: Cancer; Drug resistance; Kinase inhibitor; SNP
Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy by Kohji Noguchi; Kazuhiro Katayama; Junko Mitsuhashi; Yoshikazu Sugimoto (pp. 26-33).
The breast cancer resistance protein, BCRP/ABCG2, is a half-molecule ATP-binding cassette transporter that facilitates the efflux of various anticancer agents from the cell, including 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. The expression of BCRP can thus confer a multidrug resistance phenotype in cancer cells, and its transporter activity is involved in the in vivo efficacy of chemotherapeutic agents. Thus, the elucidation of the substrate preferences and structural relationships of BCRP is essential to understanding its in vivo functions during chemotherapeutic treatments. Single nucleotide polymorphisms (SNPs) have also been found to be key factors in determining the efficacy of chemotherapeutics, and those therapeutics that inhibit BCRP activity, such as the SNP that results in a C421A mutant, may result in unexpected side effects of the BCRP- anticancer drugs interaction even at normal dosages. In order to modulate the BCRP activity during chemotherapy, various compounds have been tested as inhibitors of this protein. Estrogenic compounds including estrone, several tamoxifen derivatives in addition to phytoestrogens and flavonoids have been shown to reverse BCRP-mediated drug resistance. Intriguingly, recently developed molecular targeted cancer drugs, such as the tyrosine kinase inhibitors imatinib mesylate, gefitinib and others, can also interact with BCRP. Since both functional SNPs and inhibitory agents of BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of its substrate drugs, BCRP activity is an important consideration in the development of molecular targeted chemotherapeutics.
Keywords: Cancer; Drug resistance; Kinase inhibitor; SNP
QSAR analysis and molecular modeling of ABCG2-specific inhibitors by E. Nicolle; A. Boumendjel; S. Macalou; E. Genoux; A. Ahmed-Belkacem; P.-A. Carrupt; A. Di Pietro (pp. 34-46).
In addition to its critical role is controlling drug availability and protecting sensitive organs and stem cells through cellular detoxification, breast cancer resistance protein (BCRP/ABCG2) plays an important role in cancer cell resistance to chemotherapy, together with P-glycoprotein/ABCB1. A main approach to abolish multidrug resistance is to find out specific inhibitors of the drug-efflux activity, able to chemosensitize cancer cell proliferation. Many efforts have been primarily focused on ABCB1, discovered thirty years ago, whereas very few studies have concerned ABCG2, identified much more recently. This review describes the main types of inhibitors presently known for ABCG2, and how quantitative structure–activity relationship analysis among series of compounds may lead to build up molecular models and pharmacophores allowing to design lead inhibitors as future candidates for clinical trials. A special attention is drawn on flavonoids which constitute a structurally-diverse class of compounds, well suited to identify potent ABCG2-specific inhibitors.
Keywords: QSAR; Pharmacophore; Inhibitor; Substrate; Multidrug resistance; ABCG2; Breast cancer resistance protein (BCRP); Flavonoids; Chemotherapy
QSAR analysis and molecular modeling of ABCG2-specific inhibitors by E. Nicolle; A. Boumendjel; S. Macalou; E. Genoux; A. Ahmed-Belkacem; P.-A. Carrupt; A. Di Pietro (pp. 34-46).
In addition to its critical role is controlling drug availability and protecting sensitive organs and stem cells through cellular detoxification, breast cancer resistance protein (BCRP/ABCG2) plays an important role in cancer cell resistance to chemotherapy, together with P-glycoprotein/ABCB1. A main approach to abolish multidrug resistance is to find out specific inhibitors of the drug-efflux activity, able to chemosensitize cancer cell proliferation. Many efforts have been primarily focused on ABCB1, discovered thirty years ago, whereas very few studies have concerned ABCG2, identified much more recently. This review describes the main types of inhibitors presently known for ABCG2, and how quantitative structure–activity relationship analysis among series of compounds may lead to build up molecular models and pharmacophores allowing to design lead inhibitors as future candidates for clinical trials. A special attention is drawn on flavonoids which constitute a structurally-diverse class of compounds, well suited to identify potent ABCG2-specific inhibitors.
Keywords: QSAR; Pharmacophore; Inhibitor; Substrate; Multidrug resistance; ABCG2; Breast cancer resistance protein (BCRP); Flavonoids; Chemotherapy
Ins and outs of the ABCG2 multidrug transporter: An update on in vitro functional assays by Hegedus Csilla Hegedűs; Szakacs Gergely Szakács; László Homolya; Orban Tamás I. Orbán; Ágnes Telbisz; Márton Jani; Balázs Sarkadi (pp. 47-56).
The major aim of this chapter is to provide a critical overview of the in vitro methods available for studying the function of the ABCG2 multidrug transporter protein. When describing the most applicable assay systems, in each case we present a short overview relevant to ABC multidrug transporters in general, and then we concentrate on the tools applicable to analysis of substrate-drug interactions, the effects of potential activators and inhibitors, and the role of polymorphisms of the ABCG2 transporter. Throughout this chapter we focus on recently developed assay systems, which may provide new possibilities for analyzing the pharmacological aspects of this medically important protein.
Keywords: Abbreviations; ABC; ATP Binding Cassette; ABCP placenta-specific; ABC transporter; ADME-Tox; absorption, distribution, metabolism, excretion, and toxicology; BCRP; breast cancer resistance protein; MXR; mitoxantrone resistance protein; MDR; Multidrug Resistance; NBD; Nucleotide Binding Domain; Pgp; P-glycoprotein; TMD; Transmembrane Domain.ABCG2; Multidrug resistance; ADME-Tox; Membrane-based assays; Cellular assays; Conformation sensitive antibody; Fluorescent proteins
Ins and outs of the ABCG2 multidrug transporter: An update on in vitro functional assays by Hegedus Csilla Hegedűs; Szakacs Gergely Szakács; László Homolya; Orban Tamás I. Orbán; Ágnes Telbisz; Márton Jani; Balázs Sarkadi (pp. 47-56).
The major aim of this chapter is to provide a critical overview of the in vitro methods available for studying the function of the ABCG2 multidrug transporter protein. When describing the most applicable assay systems, in each case we present a short overview relevant to ABC multidrug transporters in general, and then we concentrate on the tools applicable to analysis of substrate-drug interactions, the effects of potential activators and inhibitors, and the role of polymorphisms of the ABCG2 transporter. Throughout this chapter we focus on recently developed assay systems, which may provide new possibilities for analyzing the pharmacological aspects of this medically important protein.
Keywords: Abbreviations; ABC; ATP Binding Cassette; ABCP placenta-specific; ABC transporter; ADME-Tox; absorption, distribution, metabolism, excretion, and toxicology; BCRP; breast cancer resistance protein; MXR; mitoxantrone resistance protein; MDR; Multidrug Resistance; NBD; Nucleotide Binding Domain; Pgp; P-glycoprotein; TMD; Transmembrane Domain.ABCG2; Multidrug resistance; ADME-Tox; Membrane-based assays; Cellular assays; Conformation sensitive antibody; Fluorescent proteins
Purification and structural analyses of ABCG2 by Christopher A. McDevitt; Richard Collins; Ian D. Kerr; Richard Callaghan (pp. 57-65).
ABCG2 is best known as a multidrug transporter capable of conferring resistance to cancer cells. However, the protein is also inherently expressed in numerous barrier tissues and intriguingly within hematopoietic stem cells. Unlike its partners ABCB1 and ABCC1, there is considerably less information available on the molecular mechanism of ABCG2. The transporter has a distinct topology and is presumed to function as a homodimer. However, a number of biochemical studies have presented data to suggest that the protein adopts higher order oligomers. This review focuses on this controversial issue with particular reference to findings from low resolution structural data. In addition, a number of molecular models of ABCG2 based on high resolution structures of bacterial ABC transporters have recently become available and are critically assessed. ABCG2 is a structurally distinct member of the triumvirate of human multidrug transporters and continues to evade description of a unifying molecular mechanism.
Keywords: Multidrug resistance; Multidrug efflux; Membrane protein solubilisation; Electron microscopy; Oligomerisation; Molecular modelling; Structural analysis
Purification and structural analyses of ABCG2 by Christopher A. McDevitt; Richard Collins; Ian D. Kerr; Richard Callaghan (pp. 57-65).
ABCG2 is best known as a multidrug transporter capable of conferring resistance to cancer cells. However, the protein is also inherently expressed in numerous barrier tissues and intriguingly within hematopoietic stem cells. Unlike its partners ABCB1 and ABCC1, there is considerably less information available on the molecular mechanism of ABCG2. The transporter has a distinct topology and is presumed to function as a homodimer. However, a number of biochemical studies have presented data to suggest that the protein adopts higher order oligomers. This review focuses on this controversial issue with particular reference to findings from low resolution structural data. In addition, a number of molecular models of ABCG2 based on high resolution structures of bacterial ABC transporters have recently become available and are critically assessed. ABCG2 is a structurally distinct member of the triumvirate of human multidrug transporters and continues to evade description of a unifying molecular mechanism.
Keywords: Multidrug resistance; Multidrug efflux; Membrane protein solubilisation; Electron microscopy; Oligomerisation; Molecular modelling; Structural analysis
Quality control of human ABCG2 protein in the endoplasmic reticulum: Ubiquitination and proteasomal degradation by Kanako Wakabayashi-Nakao; Ai Tamura; Tomoka Furukawa; Hiroshi Nakagawa; Toshihisa Ishikawa (pp. 66-72).
Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP/MXR/ABCP) is a plasma membrane protein carrying intra- and inter-molecular disulfide bonds and an N-linked glycan. Both disulfide bond formation and N-glycosylation are critical check points determining the stability and degradation fate of ABCG2 protein in the endoplasmic reticulum (ER). Misfolded ABCG2 protein without those post-translational modifications is removed from the ER by retrotranslocation to the cytosol compartment, ubiquitination by ubiquitin ligase, and finally degradation by proteasomes. Certain non-synonymous SNP variants of ABCG2 undergo such ER-associated degradation (ERAD).
Keywords: ERAD; Ubiquitin; Proteasome; Endosome; Lysosome; N; -glycosylation; Disulfide bond
Quality control of human ABCG2 protein in the endoplasmic reticulum: Ubiquitination and proteasomal degradation by Kanako Wakabayashi-Nakao; Ai Tamura; Tomoka Furukawa; Hiroshi Nakagawa; Toshihisa Ishikawa (pp. 66-72).
Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP/MXR/ABCP) is a plasma membrane protein carrying intra- and inter-molecular disulfide bonds and an N-linked glycan. Both disulfide bond formation and N-glycosylation are critical check points determining the stability and degradation fate of ABCG2 protein in the endoplasmic reticulum (ER). Misfolded ABCG2 protein without those post-translational modifications is removed from the ER by retrotranslocation to the cytosol compartment, ubiquitination by ubiquitin ligase, and finally degradation by proteasomes. Certain non-synonymous SNP variants of ABCG2 undergo such ER-associated degradation (ERAD).
Keywords: ERAD; Ubiquitin; Proteasome; Endosome; Lysosome; N; -glycosylation; Disulfide bond