ABCB1, ABC20, CD243, CLCS, GP170, MDR1, P-GP, PGY1, ATP binding cassette subfamily B member 1, P-glycoprotein, P-gp, Pgp
External IDs
MGI: 97570 HomoloGene: 55496 GeneCards: ABCB1
Gene location (Mouse)
Chr.
Chromosome 5 (mouse)[1]
Band
5 A1|5 3.43 cM
Start
8,660,077 bp[1]
End
8,748,575 bp[1]
RNA expression pattern
More reference expression data
Gene ontology
Molecular function
• ATPase activity, coupled to transmembrane movement of substances • nucleotide binding • transporter activity • ATPase activity • protein binding • hydrolase activity • ATP binding • xenobiotic-transporting ATPase activity • phosphatidylethanolamine-translocating ATPase activity • phosphatidylcholine-translocating ATPase activity • ceramide-translocating ATPase activity
Cellular component
• integral component of membrane • membrane • plasma membrane • cell surface • extracellular exosome • apical plasma membrane
Biological process
• stem cell proliferation • xenobiotic transport • G2/M transition of mitotic cell cycle • transmembrane transport • response to drug • phospholipid translocation • drug transmembrane transport • ceramide translocation • regulation of response to osmotic stress • positive regulation of anion channel activity • regulation of chloride transport • transport • ATP hydrolysis coupled ion transmembrane transport
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
5243
18671
Ensembl
n/a
ENSMUSG00000040584
UniProt
P08183
P21447
RefSeq (mRNA)
NM_000927
NM_011076
RefSeq (protein)
NP_000918 NP_001335873 NP_001335874 NP_001335875
NP_035206
Location (UCSC)
n/a
Chr 5: 8.66 – 8.75 Mb
PubMed search
[2]
[3]
Wikidata
View/Edit Human
View/Edit Mouse
ABCB1 at EBI Gene Expression Atlas
ABCB1 is differentially expressed in 97 experiments [93 up/106 dn]: 26 organism parts: kidney [2 up/0 dn], bone marrow [0 up/2 dn], ...; 29 disease states: normal [10 up/3 dn], glioblastoma [0 up/2 dn], ...; 30 cell types, 22 cell lines, 11 compound treatments and 16 other conditions.
Factor Value
Factor
Up/Down
Legend: - number of studies the gene is up/down in
Normal
Disease state
10/3
None
Compound treatment
3/0
Stromal cell
Cell type
1/2
Kidney
Cell type
2/0
MDA-MB-231
Cell line
0/2
Glioblastoma
Disease state
0/2
Epithelial cell
Cell type
0/2
HeLa
Cell line
0/2
Primary
Disease staging
2/0
Bone marrow
Organism part
0/2
ABCB1 expression data in ATLAS
P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity. It exists in animals, fungi, and bacteria, and it likely evolved as a defense mechanism against harmful substances.
P-gp is extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics (such as toxins or drugs) back into the intestinal lumen, in liver cells where it pumps them into bile ducts, in the cells of the proximal tubule of the kidney where it pumps them into urinary filtrate (in the proximal tubule), and in the capillary endothelial cells composing the blood–brain barrier and blood-testis barrier, where it pumps them back into the capillaries.
P-gp is a glycoprotein that in humans is encoded by the ABCB1 gene.[4] P-gp is a well-characterized ABC-transporter (which transports a wide variety of substrates across extra- and intracellular membranes) of the MDR/TAP subfamily.[5] The normal excretion of xenobiotics back into the gut lumen by P-gp pharmacokinetically reduces the efficacy of some pharmaceutical drugs (which are said to be P-gp substrates). In addition, some cancer cells also express large amounts of P-gp, further amplifying that effect and rendering these cancers multidrug resistant. Many drugs inhibit P-gp, typically incidentally rather than as their main mechanism of action; some foods do as well.[6] Any such substance can sometimes be called a P-gp inhibitor.
P-gp was discovered in 1971 by Victor Ling.
Contents
1Gene
2Protein
3Species, tissue, and subcellular distribution
4Function
5Regulation of expression and function of P-gp in cancer cells
6Clinical significance
6.1Drug interactions
6.2Diseases (non-Cancer)
6.3Cancer
7History
8Research
9Single nucleotide polymorphism rs1045642
10References
11Further reading
12External links
Gene
A 2015 review of polymorphisms in ABCB1 found that "the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance."[7]
Protein
P-gp is a 170 kDa transmembrane glycoprotein, which includes 10-15 kDa of N-terminal glycosylation. The N-terminal half of the molecule contains 6 transmembrane domains, followed by a large cytoplasmic domain with an ATP-binding site, and then a second section with 6 transmembrane domains and an ATP-binding site that shows over 65% of amino acid similarity with the first half of the polypeptide.[8] In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U).[9] The structure was derived from the mouse MDR3 gene product heterologously expressed in Pichia pastoris yeast. The structure of mouse P-gp is similar to structures of the bacterial ABC transporter MsbA (3B5W and 3B5X)[10] that adopt an inward facing conformation that is believed to be important for binding substrate along the inner leaflet of the membrane. Additional structures (3G60 and 3G61) of P-gp were also solved revealing the binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding pocket of P-gp is lined with aromatic amino acid side chains.
Through Molecular Dynamic (MD) simulations, this sequence was proved to have a direct impact in the transporter's structural stability (in the nucleotide-binding domains) and defining a lower boundary for the internal drug-binding pocket.[11]
Species, tissue, and subcellular distribution
P-gp is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum.[12] P-gp is also found in brain capillary endothelial cells.[13]
Function
Substrate enters P-gp either from an opening within the inner leaflet of the membrane or from an opening at the cytoplasmic side of the protein. ATP binds at the cytoplasmic side of the protein. Following binding of each, ATP hydrolysis shifts the substrate into a position to be excreted from the cell. Release of the phosphate (from the original ATP molecule) occurs concurrently with substrate excretion. ADP is released, and a new molecule of ATP binds to the secondary ATP-binding site. Hydrolysis and release of ADP and a phosphate molecule resets the protein, so that the process can start again.
The protein belongs to the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. P-gp is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood–brain barrier. Mutations in this gene are associated with colchicine resistance and Inflammatory bowel disease 13. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [14]
P-gp transports various substrates across the cell membrane including:
Drugs such as colchicine, desloratadine[15], tacrolimus and quinidine.
Chemotherapeutic agents such as topoisomerase inhibitors (i.e. etoposide, doxorubicin), microtubule-targeted drugs (i.e. vinblastine), and tyrosine kinase inhibitors (i.e. gefitinib, sunitinib).
Lipids
Steroids
Xenobiotics
Peptides
Bilirubin
Cardiac glycosides like digoxin
Immunosuppressive agents
Glucocorticoids like dexamethasone
HIV-type 1 antiretroviral therapy agents like protease inhibitors and nonnucleoside reverse transcriptase inhibitors.
Its ability to transport the above substrates accounts for the many roles of P-gp including:
Regulating the distribution and bioavailability of drugs
Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, and therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression
Active cellular transport of antineoplastics resulting in multidrug resistance to these drugs
The removal of toxic metabolites and xenobiotics from cells into urine, bile, and the intestinal lumen
The transport of compounds out of the brain across the blood–brain barrier
Digoxin uptake
Prevention of ivermectin and loperamide entry into the central nervous system
The migration of dendritic cells
Protection of hematopoietic stem cells from toxins.[5]
It is inhibited by many drugs, such as amiodarone, azithromycin, captopril, clarithromycin, cyclosporine, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar, and verapamil.[16]
Regulation of expression and function of P-gp in cancer cells
At transcriptional level, the expression of P-gp has been intensively studied, and numerous transcriptional factors and pathways are known to play roles. A variety of transcriptional factors, such as p53,[17] YB-1,[18] and NF-𝜅B[19] are involved in the direct regulation of P-gp by binding to the promoter regions of P-gp gene. Many cell signaling pathways are also involved in transcriptional regulation of P-gp. For example, PI3K/Akt pathway[18] and Wnt/ β-catenin pathway[20] were reported to positively regulate the expression of P-gp. Mitogen-activated protein kinase (MAPK) signaling pathways includes three pathways: the classical MAPK/ERK pathway, p38 MAPK pathway, and c-Jun N-terminal kinase (JNK) pathway, all of which were reported to have implications in the regulation of the expression of P-gp. Studies suggested that MAPK/ERK pathway is involved in the positive regulation of P-gp;[21] p38 MAPK pathway negatively regulates the expression of P-gp gene;[22] JNK pathway were reported to be involved in both positive regulation and negative regulation of P-gp.[23][24]
After year 2008, MicroRNAs (miRNAs) are identified as new players in regulating the expression of P-gp in both transcriptional and post-transcriptional levels. Some members of miRNAs decrease the expression of P-gp. For example, miR-200c down-regulates the expression of P-gp through JNK signaling pathway[23] or ZEB1 and ZEB2;[25] miR-145 down-regulates mRNA of P-gp by directly binding to the 3'-UTR of the gene of P-gp and thus suppresses the translation of P-gp.[26] Some other members of miRNAs increase the expression of P-gp. For example, miR-27a up-regulates P-gp expression by suppressing Raf kinase inhibitor protein (RKIP);[27] alternatively, miR-27a can also directly bind to the promoter of P-gp gene, which works in a similar way with the mechanism of action of transcriptional factors.[28]
The expression of P-gp is also regulated by post-translational events, such as post-transcriptional modification, degradation, and intracellular trafficking of P-gp. Pim-1 protects P-gp from ubiquitination and the following degradation in proteasome.[29] Small GTPases Rab5 down-regulates the endocytotic trafficking of P-gp and thus increases the functional P-gp level on the cell membrane;[30] while Small GTPases Rab4 work in an opposite way: Rab4 down-regulates the exocytotic trafficking of P-gp from intracellular compartments to cell membrane, and therefore decreases the functional P-gp level on cell membrane.[31]
Clinical significance
Drug interactions
Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole[32], lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine[33], saquinavir[32], sertraline, quinidine, tamoxifen, verapamil[34], and duloxetine.[35] Elacridar & CP 100356 are other common Pgp inhibitors. Zosuquidar & Tariquidar was also developed with this in mind. Lastly, Valspodar & Reversan are other examples of such actors.
Common pharmacological inducers of P-glycoprotein include carbamazepine, dexamethasone, doxorubicin, nefazodone, phenobarbital, phenytoin, prazocin, rifampin, St. Johns wort, tenofovir, tipranavir, trazodone, and vinblastine.[36]
Substrates of P-glycoprotein are susceptible to changes in pharmacokinetics due to drug interactions with P-gp inhibitors or inducers. Some of these substrates include colchicine, cyclosporine, dabigatran[33], digoxin, diltiazem[37], fexofenadine, indinavir, morphine, and sirolimus.[32]
Diseases (non-Cancer)
Decreased P-gp expression has been found in Alzheimer’s disease brains.[38]
Altered P-gp function has also been linked to inflammatory bowel diseases (IBD),[39] however, due to its ambivalent effects in intestinal inflammation many questions remain so far unanswered.[40] While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD.[40] Mice deficient in MDR1A develop chronic intestinal inflammation spontaneously, which appears to resemble human ulcerative colitis.[41]
Cancer
P-gp efflux activity is capable of lowering intracellular concentrations of otherwise beneficial compounds, such as chemotherapeutics and other medications, to sub-therapeutic levels. Consequently, P-gp overexpression is one of the main mechanisms behind decreased intracellular drug accumulation and development of multidrug resistance in human multidrug-resistant (MDR) cancers.[42][43]
History
P-gp was first characterized in 1976. P-gp was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer cells that had developed resistance to cytotoxic drugs.[5][44]
The structure of mouse P-gp, which has 87% sequence identity to human P-gp, was resolved by x-ray crystallography in 2009.[9]. The first structure of human P-gp was solved in 2018, with the protein in its ATP-bound, outward-facing conformation. [45]
Research
Radioactive verapamil can be used for measuring P-gp function with positron emission tomography.[46]
P-gp is also used to differentiate transitional B cells from naive B cells. Dyes such as rhodamine 123 and MitoTracker dyes from Invitrogen can be used to make this differentiation.[47]
Single nucleotide polymorphism rs1045642
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References
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^Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT (July 2015). "Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature". Clinical Pharmacokinetics. 54 (7): 709–35. doi:10.1007/s40262-015-0267-1. PMID 25860377.
^Franck Viguié (1998-03-01). "ABCB1". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-03-02.
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^Bark H, Choi CH (May 2010). "PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB". Cancer Chemotherapy and Pharmacology. 65 (6): 1131–6. doi:10.1007/s00280-009-1121-7. PMID 19763573.
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^Zhang H, Li M, Han Y, Hong L, Gong T, Sun L, Zheng X (September 2010). "Down-regulation of miR-27a might reverse multidrug resistance of esophageal squamous cell carcinoma". Digestive Diseases and Sciences. 55 (9): 2545–51. doi:10.1007/s10620-009-1051-6. PMID 19960259.
^Xie Y, Burcu M, Linn DE, Qiu Y, Baer MR (August 2010). "Pim-1 kinase protects P-glycoprotein from degradation and enables its glycosylation and cell surface expression". Molecular Pharmacology. 78 (2): 310–8. doi:10.1124/mol.109.061713. PMID 20460432.
^Fu D, van Dam EM, Brymora A, Duggin IG, Robinson PJ, Roufogalis BD (July 2007). "The small GTPases Rab5 and RalA regulate intracellular traffic of P-glycoprotein". Biochimica et Biophysica Acta. 1773 (7): 1062–72. doi:10.1016/j.bbamcr.2007.03.023. PMID 17524504.
^Ferrándiz-Huertas C, Fernández-Carvajal A, Ferrer-Montiel A (January 2011). "Rab4 interacts with the human P-glycoprotein and modulates its surface expression in multidrug resistant K562 cells". International Journal of Cancer. 128 (1): 192–205. doi:10.1002/ijc.25310. PMID 20209493.
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^Srivalli, KMR; Lakshmi, PK (July 2012). "Overview of P-glycoprotein inhibitors: a rational outlook". Brazilian Journal of Pharmaceutical Sciences. 48 (3): 353–367. doi:10.1590/S1984-82502012000300002.
^Ruike Z, Junhua C, Wenxing P (November 2010). "In vitro and in vivo evaluation of the effects of duloxetine on P-gp function". Human Psychopharmacology. 25 (7–8): 553–9. doi:10.1002/hup.1152. PMID 21312289.
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^van Assema DM, van Berckel BN (2016). "Blood-Brain Barrier ABC-transporter P-glycoprotein in Alzheimer's Disease: Still a Suspect?". Current Pharmaceutical Design. 22 (38): 5808–5816. doi:10.2174/1381612822666160804094544. PMID 27494062.
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^ abCario E (March 2017). "P-glycoprotein multidrug transporter in inflammatory bowel diseases: More questions than answers". World Journal of Gastroenterology. 23 (9): 1513–1520. doi:10.3748/wjg.v23.i9.1513. PMC 5340804. PMID 28321153.
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^Luurtsema G, Windhorst AD, Mooijer MP, Herscheid A, Lammertsma AA, Franssen EJ (2002). "Fully automated high yield synthesis of (R)- and (S)-[C-11]verapamil for measuring P-glycoprotein function with positron emission tomography". Journal of Labelled Compounds and Radiopharmaceuticals. 45 (14): 1199–1207. doi:10.1002/jlcr.632.
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Further reading
Kumar YS, Adukondalu D, Sathish D, Vishnu YV, Ramesh G, Latha AB, Reddy PC, Sarangapani M, Rao YM (2010). "P-Glycoprotein- and cytochrome P-450-mediated herbal drug interactions". Drug Metabolism and Drug Interactions. 25 (1–4): 3–16. doi:10.1515/DMDI.2010.006. PMID 21417789.
Kim Y, Chen J (February 2018). "Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation". Science. 359 (6378): 915–919. doi:10.1126/science.aar7389. PMID 29371429.
External links
Wikimedia Commons has media related to P-glycoprotein.
P-Glycoprotein at the US National Library of Medicine Medical Subject Headings (MeSH)
ABCB1 human gene location in the UCSC Genome Browser.
ABCB1 human gene details in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
v
t
e
Membrane proteins, carrier proteins: membrane transport proteins ABC-transporter (TC 3A1)
A
A1
A2
A3
A4
A7
A8
A12
A13
B
B1
B2-3 (B2
B3)
B4
B5
B6
B7
B9
B11
C
C1
C2
C3
C4
C5
C6
C7
C8-9 (C8, C9)
C10
C11
C13
D
D1
D2
D3
D4
E
E1
F
F1
F2
G
G1
G2
G4
Sterolin (G5, G8)
see also ABC transporter disorders
v
t
e
Proteins: clusters of differentiation (see also list of human clusters of differentiation)
1-50
CD1
a-c
1A
1D
1E
CD2
CD3
γ
δ
ε
CD4
CD5
CD6
CD7
CD8
a
CD9
CD10
CD11
a
b
c
d
CD13
CD14
CD15
CD16
A
B
CD18
CD19
CD20
CD21
CD22
CD23
CD24
CD25
CD26
CD27
CD28
CD29
CD30
CD31
CD32
A
B
CD33
CD34
CD35
CD36
CD37
CD38
CD39
CD40
CD41
CD42
a
b
c
d
CD43
CD44
CD45
CD46
CD47
CD48
CD49
a
b
c
d
e
f
CD50
51-100
CD51
CD52
CD53
CD54
CD55
CD56
CD57
CD58
CD59
CD61
CD62
E
L
P
CD63
CD64
A
B
C
CD66
a
b
c
d
e
f
CD68
CD69
CD70
CD71
CD72
CD73
CD74
CD78
CD79
a
b
CD80
CD81
CD82
CD83
CD84
CD85
a
d
e
h
j
k
CD86
CD87
CD88
CD89
CD90
CD91 - CD92
CD93
CD94
CD95
CD96
CD97
CD98
CD99
CD100
101-150
CD101
CD102
CD103
CD104
CD105
CD106
CD107
a
b
CD108
CD109
CD110
CD111
CD112
CD113
CD114
CD115
CD116
CD117
CD118
CD119
CD120
a
b
CD121
a
b
CD122
CD123
CD124
CD125
CD126
CD127
CD129
CD130
CD131
CD132
CD133
CD134
CD135
CD136
CD137
CD138
CD140b
CD141
CD142
CD143
CD144
CD146
CD147
CD148
CD150
151-200
CD151
CD152
CD153
CD154
CD155
CD156
a
b
c
CD157
CD158 (a
d
e
i
k)
CD159
a
c
CD160
CD161
CD162
CD163
CD164
CD166
CD167
a
b
CD168
CD169
CD170
CD171
CD172
a
b
g
CD174
CD177
CD178
CD179
a
b
CD180
CD181
CD182
CD183
CD184
CD185
CD186
CD191
CD192
CD193
CD194
CD195
CD196
CD197
CDw198
CDw199
CD200
201-250
CD201
CD202b
CD204
CD205
CD206
CD207
CD208
CD209
CDw210
a
b
CD212
CD213a
1
2
CD217
CD218 (a
b)
CD220
CD221
CD222
CD223
CD224
CD225
CD226
CD227
CD228
CD229
CD230
CD233
CD234
CD235
a
b
CD236
CD238
CD239
CD240CE
CD240D
CD241
CD243
CD244
CD246
CD247 - CD248
CD249
251-300
CD252
CD253
CD254
CD256
CD257
CD258
CD261
CD262
CD263
CD264
CD265
CD266
CD267
CD268
CD269
CD271
CD272
CD273
CD274
CD275
CD276
CD278
CD279
CD280
CD281
CD282
CD283
CD284
CD286
CD288
CD289
CD290
CD292
CDw293
CD294
CD295
CD297
CD298
CD299
301-350
CD300A
CD301
CD302
CD303
CD304
CD305
CD306
CD307
CD309
CD312
CD314
CD315
CD316
CD317
CD318
CD320
CD321
CD322
CD324
CD325
CD326
CD328
CD329
CD331
CD332
CD333
CD334
CD335
CD336
CD337
CD338
CD339
CD340
CD344
CD349
CD350
UpToDate Contents
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…the cellular level . One member, the P-glycoprotein, is encoded by the human ABCB1 gene (also called the multidrug resistant 1 or MDR1 gene, MIM *171050). P-glycoprotein enhances the energy-dependent cellular …
…renal p-glycoprotein. P-glycoprotein is an efflux pump that excretes many drugs into the intestine or proximal renal tubule, thereby lowering serum concentrations. Drugs that alter p-glycoprotein activity…
…inhibit the cytochrome P450 system component CYP3A4 or that inhibit the membrane P-glycoprotein (P-gp) drug efflux pump , which may result in dangerously increased colchicine drug levels. Parenteral …
…digoxin cannot be discontinued . A list of medicines that inhibit P-glycoprotein is provided separately Inducers of P-glycoprotein (eg, phenytoin, rifampin, etc), on the other hand, can decrease serum …
… involving 153 previously untreated patients with AML, positivity for P-glycoprotein (Pgp) did not adversely affect attainment of CR or OS unless Pgp was expressed along with lung resistance-related protein (LRP) …
English Journal
Co-encapsulation of docetaxel and cyclosporin A into SNEDDS to promote oral cancer chemotherapy.
Cui W, Zhao H, Wang C, Chen Y, Luo C, Zhang S, Sun B, He Z.
Drug delivery. 2019 Dec;26(1)542-550.
Self-nanoemulsifying drug delivery system (SNEDDS) have been considered as a promising platform for oral delivery of many BCS (biopharmaceutics classification system) class IV drugs, such as docetaxel (DTX). However, oral chemotherapy with DTX is also restricted by its active P-glycoprotein (P-gp) e
The antitumor activity of CYB-L10, a human topoisomerase IB catalytic inhibitor.
Yu Q, Chen Y, Yang H, Zhang HL, Agama K, Pommier Y, An LK.
Journal of enzyme inhibition and medicinal chemistry. 2019 Dec;34(1)818-822.
DNA topoisomerase IB (TOP1) is a validated target for discovery and development of antitumor agents. Four TOP1 poisons are clinically used for tumor treatment now. In spite of their effectiveness in solid tumors, these camptothecin (CPT) poisons suffer from many shortcomings. Therefore, many investi
In vitro modulation of multidrug resistance by pregnane steroids and in vivo inhibition of tumour development by 7α-OBz-11α(R)-OTHP-5β-pregnanedione in K562/R7 and H295R cell xenografts.
Alameh G, Emptoz-Bonneton A, Rolland de Ravel M, Matera EL, Mappus E, Balaguer P, Rocheblave L, Lomberget T, Dumontet C, Le Borgne M, Pugeat M, Grenot C, Cuilleron CY.
Journal of enzyme inhibition and medicinal chemistry. 2019 Dec;34(1)684-691.
Synthetic progesterone and 5α/β-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two P-gp-expressing human cell lines, the non-steroidogenic K562/R7 erythroleukaemia cells and the steroidogenic NCI-H295R adrenocortical carcinoma
… 2019-01-10.P-glycoprotein extrudes a large variety of xenobiotics from the cell, thereby protecting tissues from their toxic effects. … Here we report a pair of structures of homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. …
Intractable & Rare Diseases Research 8(2), 120-128, 2019
… <p>Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein first identified in low-metastatic human melanoma cell lines as a regulator of tumor growth. … We found that microglia accumulating in the white matter express an intense GPNMB immunoreactivity in both NHD and AD brains, suggesting that the accumulation of GPNMB-immunoreactive microglia is a general phenomenon in neurodegenerative brains.</p> …
