Expression, Detection, and Implication of ABC Proteins in Acute Myeloblastic Leukemia
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This chapter contains sections titled: Introduction P-glycoprotein (P-gp) ABCB1 Breast cancer resistance protein (BCRP) ABCG2 Multidrug resistance associated protein (MRP1) ABCC1 Multidrug resistance associated protein (MRP1) ABCC3 ABCA3 Future perspectives ReferencesKeywords:
Abcg2
ABCC1
P-glycoprotein
Acute myeloblastic leukemia
Multidrug Resistance-Associated Proteins
Abcg2
P-glycoprotein
ABCC1
Multidrug Resistance-Associated Proteins
Efflux
Solute carrier family
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Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.
Drug Development
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Abcg2
Efflux
P-glycoprotein
Caco-2
Multidrug Resistance-Associated Proteins
Passive transport
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2300 Multidrug resistance (MDR) is a major obstacle in the successful application of chemotherapy. The overexpression of ABC transporters, Pgp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2, has been a well-known indicator of MDR. However, the importance of ABC transporters in MDR, and the mechanism of their upregulation have not been fully elucidated. The aim of this study is to examine the role of Notch1 in the expression of the multidrug resistance protein, MRP1/ABCC1. Notch1 is an enzymatic cleavable type I transmembrane protein, which is also known as an intracellular transcriptional regulator involved in regulating cell fate, apoptosis, proliferation and migration. We evaluated the levels of transmembrane Notch1 (N1 TM ) in cancer cell lines, such as CEM/VLB 100 , CEM/VM1-5, and BeWo known to overexpress the ABC transporters, Pgp, MRP1 and BCRP, respectively. Interestingly, we found an inverse relationship between the expression of Notch1 and MRP1/ABCC1 in the etoposide (VP16)-resistant CEM/VM1-5 cells and parental CEM cells. To investigate whether this inverse expression of N1 TM and MRP1 is associated with etoposide resistance, we used another cell model, VP-16-resistant MCF7/VP and its drug sensitive parents, MCF7/WT, and observed the same inverse relationship: low N1 TM but high MRP1 in the resistant MCF7/VP cells, compared to the parental cells. We hypothesize that Notch1 is one of the biological factors involved in MRP1 expression in the drug resistant cells. To understand the mechanism by which Notch1 may regulate MRP1, we measured the level and activity of intracellular Notch1 (ICN1) in MCF7/WT and MCF7/VP. As opposed to N1 TM , there were no detectable differences in the levels of ICN1 between MCF7/WT and MCF7/VP. However, the activity of ICN1 in MCF7/VP was about 1.5-times higher than MCF7/WT, as measured by CBF1 promoter assay. To further verify the effect of ICN1 on MRP1 expression, we blocked the generation of ICN1 in MCF7/WT and MCF7/VP with DAPT, a gama-secretase inhibitor (GSI). We observed a dose-dependent reduction of both ICN1 and MRP1 expression in the MCF7/VP cells but not in the parental cells, suggesting a possible role for ICN1 in the overexpression of MRP1 in drug resistant cells. We next measured the level of presenilin 1 (PSEN1), which is a main proteolytic enzyme involved in the generation of ICN1, and observed increased levels of PSEN1 in MCF7/VP. We conclude that etoposide-resistant cells show faster processing of ICN1, possibly via PSEN1 overexpression, and that this is associated with MRP1 upregulation. This MRP1 upregulation can be blocked by GSI, suggesting a therapeutic possibility to prevent the development of MDR. (This work was supported in part by grant CA-40570 [to WTB] and in part by the University of Illinois at Chicago)
ABCC1
Abcg2
Multidrug Resistance-Associated Proteins
Rhodamine 123
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The food and dietary supplements we consume contain a wide variety of plant secondary metabolites and other compounds, which, like drugs, can be absorbed, metabolized, distributed, and excreted from the body. In the intestine, these compounds can interact with transport proteins such as the multidrug resistance associated protein 2 (MRP2, ABCC2) and the breast cancer resistance protein (BCRP, ABCG2) that regulate the absorption of drugs and other compounds. Inhibition of these transporters by dietary components could lead to increased exposure and adverse effects of concomitantly administered drugs. Therefore, we screened a library of 124 natural compounds and their derivatives using the vesicular transport assay to evaluate their inhibitory potential on MRP2 and BCRP. Of the library compounds, 36% were identified as BCRP inhibitors, whereas the number was only 3.2% for MRP2. BCRP inhibitors are described by higher molecular weight, number of rings, aromaticity, and LogD7.4 than noninhibitors. IC50 values were measured for six dual inhibitors, among which three novel inhibitors, gossypin, nordihydroguaiaretic acid, and octyl gallate, were identified. Our results confirm that flavonoids are avid inhibitors of BCRP, and flavones and flavonols appear to be important subclasses of flavonoids for this inhibition. The strong inhibition of BCRP transport by some compounds suggests that their presence at high levels in the diet could cause food-drug interactions, but this seems to be a minor cause of concern for MRP2.
Abcg2
Multidrug Resistance-Associated Proteins
ABCC1
IC50
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Until recently, it was generally believed that the transport of various organic anions across the bile canalicular membrane was mainly mediated by multidrug resistance-associated protein 2 (MRP2/ABCC2). However, a number of new reports have shown that some organic anions are also substrates of multidrug resistance 1 (MDR1/ABCB1) and/or breast cancer resistance protein (BCRP/ABCG2), implying MDR1 and BCRP could also be involved in the biliary excretion of organic anions in humans. In the present study, we constructed new double-transfected Madin-Darby canine kidney II (MDCKII) cells expressing organic anion-transporting polypeptide 1B1 (OATP1B1)/MDR1 and OATP1B1/BCRP, and we investigated the transcellular transport of four kinds of organic anions, estradiol-17β-d-glucuronide (EG), estrone-3-sulfate (ES), pravastatin (PRA), and cerivastatin (CER), to identify which efflux transporters mediate the biliary excretion of compounds using double-transfected cells. We observed the vectorial transport of EG and ES in all the double transfectants. MRP2 showed the highest efflux clearance of EG among these efflux transporters, whereas BCRP-mediated clearance of ES was the highest in these double transfectants. In addition, two kinds of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, CER and PRA, were also substrates of all these efflux transporters. The rank order of the efflux clearance of PRA mediated by each transporter was the same as that of EG, whereas the contribution of MDR1 to the efflux of CER was relatively greater than for PRA. This experimental system is very useful for identifying which transporters are involved in the biliary excretion of organic anions that cannot easily penetrate the plasma membrane.
Abcg2
Efflux
Organic anion-transporting polypeptide
Organic anion
Estrone sulfate
Multidrug Resistance-Associated Proteins
ABCC1
Probenecid
Renal physiology
Transport protein
Paracellular transport
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Overexpression of ABC drug transporters can cause multidrug resistance (MDR) in cancer cells, which is a major obstacle in the success of cancer chemotherapy. Our study revealed a correlation between the expression of invasive breast cancer resistance-associated proteins, such as P-glycoprotein (ABCB1), MRP2 (ABCC2), BCRP (ABCG2) in tumor cells and pathologic response to neoadjuvant chemotherapy. The response to neoadjuvant chemotherapy was shown to be associated with a lack of BCRP expression in tumor cells. The pathologic tumor response was correlated with the presence of positive MRP2 expression and the expression level of P-glycoprotein in cells of invasive breast cancer.
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P-glycoprotein
Multidrug Resistance-Associated Proteins
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P-Glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are the three major ABC transport proteins conferring resistance to many structurally diverse anticancer agents, leading to the phenomenon called multidrug resistance (MDR). Much effort has been put into the development of clinically useful compounds to reverse MDR. Broad-spectrum inhibitors of ABC transport proteins can be of great use in cancers that simultaneously coexpress two or three transporters. In this work, we continued our effort to generate new, potent, nontoxic, and multiply effective inhibitors of the three major ABC transporters. The best compound was active in a very low micromolar concentration range against all three transporters and restored sensitivity toward daunorubicin (P-gp and MRP1) and SN-38 (BCRP) in A2780/ADR (P-gp), H69AR (MRP1), and MDCK II BCRP (BCRP) cells. Additionally, the compound is a noncompetitive inhibitor of daunorubicin (MRP1), calcein AM (P-gp), and pheophorbide A (BCRP) transport.
Abcg2
ABCC1
Daunorubicin
P-glycoprotein
Multidrug Resistance-Associated Proteins
Pheophorbide A
Efflux
Mediated transport
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SY31-1 Our research focuses on genes and proteins that cause drug resistance in tumors, and/or influence the pharmacological and toxicological behavior of anticancer and many other drugs and toxins, including carcinogens. Insight into these systems may improve chemotherapy approaches for cancer as well as pharmacotherapy in a broader sense, and increase insights in factors determining susceptibility to carcinogens. To study the physiological, pharmacological and toxicological roles of the proteins involved, and their interactions, we generate and analyze knockout or transgenic mice lacking or overexpressing the relevant genes. Cell lines obtained from these mice are further used as tools to identify and characterize drug resistance genes. To date, we have primarily focused on plasma membrane proteins of the ATP binding cassette (ABC) transporter family, encompassing amongst others P-glycoprotein (P-gp or ABCB1), MRP2 (ABCC2) and BCRP (ABCG2). These proteins actively export a wide range of anticancer, anti-HIV/AIDS, and many other drugs from cells. This ATP-dependent drug extrusion can cause multidrug resistance (MDR) in tumor cells (1). P-gp, MRP2 and BCRP all localize to the apical membrane of polarized epithelial cells, resulting in vectorial transport of drug substrates, and there is considerable (albeit not complete) overlap in substrate specificity between these transporters. Expression of these transporters by cDNA transfection into polarized epithelial cell lines offers excellent tools to study their transport characteristics in vitro. In the past, we and others have generated knockout mice deficient for P-gp and Bcrp1, the murine homologue of BCRP. Experiments in P-gp and Bcrp1 knockout mice indicated that these transporters can variously protect an organism against exogenous toxins and drugs by limiting penetration of substrates into brain, testis, and fetus, by restricting uptake of orally administered substrates, and by mediating excretion of substrates via liver and intestine. Mice lacking Bcrp1 look overall normal, but they are extremely sensitive to the dietary chlorophyll breakdown product pheophorbide a, resulting in severe, sometimes lethal phototoxic lesions on light-exposed skin (2). Pheophorbide a is a porphyrin that occurs in various plant-derived foods and food supplements. Bcrp1 transports pheophorbide a and is highly efficient in limiting its uptake from ingested food. Furthermore, as predicted from previous in vivo inhibition experiments, Bcrp1 knockout mice demonstrated a 6-fold increased oral uptake, and 2-fold increased fetal penetration of topotecan. Bcrp1 knockout mice also displayed a novel type of protoporphyria: Erythrocyte levels of the heme precursor and phototoxin protoporphyrin IX were 10-fold increased. These results indicate that humans or animals with low or absent BCRP activity may be at increased risk for developing protoporphyria and diet-dependent phototoxicity, and provide a striking illustration of the importance of drug transporters in protection from toxicity of normal food constituents. The data imply that prolonged inhibition of BCRP by administration of BCRP inhibitors to patients should be monitored carefully for unexpected side effects. We have also identified a pronounced role for Bcrp1 in the pharmacokinetics of, and hence possibly protection from, dietary carcinogens (3). The food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine found in various protein-containing foods. PhIP is mutagenic and carcinogenic in rodents, and it has been implicated in human breast carcinogenesis. Humans on a normal western diet are exposed to PhIP on a daily basis. We investigated whether Bcrp1 could affect PhIP exposure of the body, as this could implicate BCRP activity in the cancer risk due to PhIP. Using polarized cell lines we found that PhIP is efficiently transported by murine Bcrp1. In vivo pharmacokinetic studies in Bcrp1 knockout mice showed that Bcrp1 effectively restricts the exposure of mice to ingested PhIP, by decreasing its uptake from the gut lumen and by mediating hepatobiliary and intestinal elimination of PhIP. Intra- or interindividual differences in BCRP activity in humans may thus also affect the exposure to PhIP and related food carcinogens, with possible implications for cancer susceptibility. We are currently extending the functional analysis of BCRP and Bcrp1 in the pharmacokinetics of several anticancer drugs and dietary carcinogens. Moreover, by more detailed analysis of expression of Bcrp1 in mice and other species we have identified several additional organs where BCRP/Bcrp1 may have physiological and pharmacologically relevant functions. Some of these newly identified functions and their implications will be discussed.
Abcg2
P-glycoprotein
ABCC1
Multidrug Resistance-Associated Proteins
Efflux
Solute carrier family
Knockout mouse
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Abcg2
Oncostatin M
Organic anion-transporting polypeptide
Multidrug Resistance-Associated Proteins
Efflux
Solute carrier family
P-glycoprotein
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