scholarly journals Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 455 ◽  
Author(s):  
Simona Dobiasová ◽  
Kateřina Řehořová ◽  
Denisa Kučerová ◽  
David Biedermann ◽  
Kristýna Káňová ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Biological Activities ◽  
Biologically Active ◽  
Cancer Drug ◽  
Optical Isomers ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Dose Dependent

Silybin is considered to be the main biologically active component of silymarin. Its oxidized derivative 2,3-dehydrosilybin typically occurs in silymarin in small, but non-negligible amounts (up to 3%). Here, we investigated in detail complex biological activities of silybin and 2,3-dehydrosilybin optical isomers. Antioxidant activities of pure stereomers A and B of silybin and 2,3-dehydrosilybin, as well as their racemic mixtures, were investigated by using oxygen radical absorption capacity (ORAC) and cellular antioxidant activity (CAA) assay. All substances efficiently reduced nitric oxide production and cytokines (TNF-α, IL-6) release in a dose-dependent manner. Multidrug resistance (MDR) modulating potential was evaluated as inhibition of P-glycoprotein (P-gp) ATPase activity and regulation of ATP-binding cassette (ABC) protein expression. All the tested compounds showed strong dose-dependent inhibition of P-gp pump. Moreover, 2,3-dehydrosilybin A (30 µM) displayed the strongest sensitization of doxorubicin-resistant ovarian carcinoma. Despite these significant effects, silybin B was the only compound acting directly upon P-gp in vitro and also downregulating the expression of respective MDR genes. This compound altered the expression of P-glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). 2,3-Dehydrosilybin AB exhibited the most effective inhibition of acetylcholinesterase activity. We can clearly postulate that silybin derivatives could serve well as modulators of a cancer drug-resistant phenotype.

Stimulation of steroid production in isolated rat Leydig cells by unknown factors in testicular fluid differs from the effects of LH or LH-releasing hormone

1986 ◽  
Vol 109 (1) ◽  
pp. 111-117 ◽  
Author(s):  
F. F. G. Rommerts ◽  
J. W. Hoogerbrugge ◽  
H. J. van der Molen
Keyword(s):  
Leydig Cells ◽  
Biological Activities ◽  
Biologically Active ◽  
Dependent Manner ◽  
Steroid Production ◽  
Releasing Hormone ◽  
Old Rats ◽  
Lh Releasing Hormone ◽  
Dose Dependent ◽  
Stimulation Of

ABSTRACT After the addition of charcoal-treated testicular fluid to Leydig cells isolated from 22-day-old rats, pregnenolone production could be increased to a maximum of tenfold within 30 min in a dose-dependent manner. Testicular fluid, but not serum, further increased pregnenolone formation threefold when pregnenolone production by Leydig cells was stimulated by the addition of LH-releasing hormone (fourfold), LH (25-fold) and 22R-hydroxycholesterol (300-fold). The effect of testicular fluid on steroid production in the presence of 22R-hydroxycholesterol was not inhibited by cycloheximide whereas cycloheximide completely inhibited the effect of LH. It appears unlikely that steroids, lipoproteins or other plasma components constitute the stimulatory agents in testicular fluid. The biologically active principles may be locally produced factors with a molecular weight > 25 000. Similar biological activities could be shown in testicular lymph from boars but not in systemic lymph from boars nor in charcoal-treated bovine follicular fluid. The presumably locally produced factor(s) may amplify the effect of LH and can thus act as a local modulator(s). J. Endocr. (1986) 109, 111–117

scholarly journals Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3364 ◽  
Author(s):  
Bruno M. F. Gonçalves ◽  
David S. P. Cardoso ◽  
Maria-José U. Ferreira
Keyword(s):  
Multidrug Resistance ◽  
Natural Product ◽  
Abc Transporter ◽  
Efflux Pumps ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Multidrug Resistance Protein 1 ◽  
P Glycoprotein ◽  
Resistance Protein

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

scholarly journals Antioxidant, Anti-Inflammatory, and Multidrug Resistance Modulation Activity of Silychristin Derivatives

Antioxidants ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 303 ◽  
Author(s):  
Jitka Viktorová ◽  
Simona Dobiasová ◽  
Kateřina Řehořová ◽  
David Biedermann ◽  
Kristýna Káňová ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
No Production ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Modulation

Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (ABCB1) and ABCG2 genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps.

scholarly journals In silico and in vitro identification of secoisolariciresinol as a re-sensitizer of P-glycoprotein-dependent doxorubicin-resistance NCI/ADR-RES cancer cells

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9163 ◽  
Author(s):  
Mohamed A. Morsy ◽  
Azza A.K. El-Sheikh ◽  
Ahmed R.N. Ibrahim ◽  
Katharigatta N. Venugopala ◽  
Mahmoud Kandeel
Keyword(s):  
Cancer Cells ◽  
Md Simulation ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Binding Domains ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Substrate Inhibitor ◽  
Dose Dependent

P-glycoprotein (P-gp) is one of the highly expressed cancer cell efflux transporters that cause the failure of chemotherapy. To reverse P-gp induced multidrug resistance, we employed a flaxseed-derived lignan; secoisolariciresinol (SECO) that acts as an inhibitor of breast cancer resistance protein; another efflux transporter that shares some substrate/inhibitor specificity with P-gp. Molecular dynamics (MD) simulation identified SECO as a possible P-gp inhibitor. Comparing root mean square deviation (RMSD) of P-gp bound with SECO with that bound to its standard inhibitor verapamil showed that fluctuations in RMSD were lower in P-gp bound to SECO demonstrating higher stability of the complex of P-gp with SECO. In addition, the superimposition of P-gp structures after MD simulation showed that the nucleotide-binding domains of P-gp bound to SECO undertook a more central closer position compared with that bound to verapamil. Using rhodamine efflux assay on NCI/ADR-RES cancer cells, SECO was confirmed as a P-gp inhibitor, where cells treated with 25 or 50 µM of SECO showed significantly higher fluorescence intensity compared to control. Using MTT assay, SECO alone showed dose-dependent cytotoxicity, where 25 or 50 µM of SECO caused significantly less NCI/ADR-RES cellular viability compared to control. Furthermore, when 50 µM of SECO was added to doxorubicin (DOX), an anticancer drug, SECO significantly enhanced DOX-induced cytotoxicity compared to DOX alone. The combination index calculated by CompuSyn software indicated synergism between DOX and SECO. Our results suggest SECO as a novel P-gp inhibitor that can re-sensitize cancer cells during DOX chemotherapy.

scholarly journals Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 357
Author(s):  
Sérgio M. Marques ◽  
Lucie Šupolíková ◽  
Lenka Molčanová ◽  
Karel Šmejkal ◽  
David Bednar ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Cancer Drug ◽  
Binding Modes ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Anti Cancer ◽  
Theoretical Predictions ◽  
Glycoprotein Inhibitors

Multidrug resistance (MDR) is a common problem when fighting cancer with chemotherapy. P-glycoprotein (P-gp, or MDR1) is an active pump responsible for the efflux of xenobiotics out of the cell, including anti-cancer drugs. It is a validated target against MDR. No crystal structure of the human P-gp is available to date, and only recently several cryo-EM structures have been solved. In this paper, we present a comprehensive computational approach that includes constructing the full-length three-dimensional structure of the human P-gp and its refinement using molecular dynamics. We assessed its flexibility and conformational diversity, compiling a dynamical ensemble that was used to dock a set of lignan compounds, previously reported as active P-gp inhibitors, and disclose their binding modes. Based on the statistical analysis of the docking results, we selected a system for performing the structure-based virtual screening of new potential P-gp inhibitors. We tested the method on a library of 87 natural flavonoids described in the literature, and 10 of those were experimentally assayed. The results reproduced the theoretical predictions only partially due to various possible factors. However, at least two of the predicted natural flavonoids were demonstrated to be effective P-gp inhibitors. They were able to increase the accumulation of doxorubicin inside the human promyelocytic leukemia HL60/MDR cells overexpressing P-gp and potentiate the antiproliferative activity of this anti-cancer drug.

scholarly journals Crystal structure of the antigen-binding fragment of a monoclonal antibody specific for the multidrug-resistance-linked ABC transporter human P-glycoprotein

2016 ◽  
Vol 72 (8) ◽  
pp. 636-641 ◽  
Author(s):  
Lothar Esser ◽  
Suneet Shukla ◽  
Fei Zhou ◽  
Suresh V. Ambudkar ◽  
Di Xia
Keyword(s):  
Monoclonal Antibody ◽  
Multidrug Resistance ◽  
Antigen Binding ◽  
Dependent Manner ◽  
X Rays ◽  
Fab Fragment ◽  
Glycoprotein P ◽  
Cell Parameters ◽  
P Glycoprotein ◽  
High Resolution Structure

P-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancers that plays important roles in the pharmacokinetics of a large number of drugs. The drug-resistance phenotype of P-gp can be modulated by the monoclonal antibody UIC2, which specifically recognizes human P-gp in a conformation-dependent manner. Here, the purification, sequence determination and high-resolution structure of the Fab fragment of UIC2 (UIC2/Fab) are reported. Purified UIC2/Fab binds human P-gp with a 1:1 stoichiometry. Crystals of UIC2/Fab are triclinic (space groupP1), with unit-cell parametersa= 40.67,b= 44.91,c= 58.09 Å, α = 97.62, β = 99.10, γ = 94.09°, and diffracted X-rays to 1.6 Å resolution. The structure was determined by molecular replacement and refined to 1.65 Å resolution. The asymmetric unit contains one molecule of UIC2/Fab, which exhibits a positively charged antigen-binding surface, suggesting that it might recognize an oppositely charged extracellular epitope of P-gp.

Ecological and physiological as well as biochemical properties of representatives of the Genus sedum L.

2014 ◽  
Vol 25 (3-4) ◽  
pp. 24-33
Author(s):  
O. I. Dzjuba ◽  
M. V. Yatsenko
Keyword(s):  
Nitric Oxide ◽  
Cell Line ◽  
Methanol Extract ◽  
Hepatoma Cell ◽  
Ethanol Extract ◽  
Biochemical Properties ◽  
Biologically Active ◽  
Hepatoma Cell Line ◽  
Dependent Manner ◽  
Dose Dependent

The article deals with the history of the study and the current state of research of physiological and biochemical properties of the plant genus Sedum that are useful for human and has been used in folk medicine for many years. It was noticed that antioxidant properties of extracts from plants S. sarmentosum, S. sempervivoides, S. takesimense were caused by the presence of phenolic compounds. Methanol extract of plants S. takesimense exhibited strong scavenging activities against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals as well as significant inhibitory effects on lipid peroxidation and low density lipoprotein (LDL) oxidation induced by a metal ion Cu2+. Various immunomodulatory activities of various fractions of plants extracts (S. dendroideum, S. kamtschaticum, S. sarmentosum, S. telephium) are observed. It was shown that the ethanol extract of S. sarmentosum and it’s fractions suppressed specific antibody and cellular responses to ovalbumin in mice. The methanol extract of plants S. sarmentosum reduced the levels of anti-inflammatory markers, such as volume of exudates, number of polymorphonuclear leukocytes, suppressed nitric oxide synthesis in activated macrophages via suppressed induction of inducible nitric oxide synthase (iNOS). Polysaccharides fractions from plants S. telephium inducing productions of tumor necrosis factor alpha (TNF-α), increasing the intensity of phagocytosis in vitro and in vivo. Methanol extract from the whole part of S. kamtschaticum strongly inhibit PGE2 production from lipopolysaccharide-induced RAW 264.7 cells, a mouse macrophage cell line via modulating activity in gene expression of the enzyme cyclooxygenase-2 (COX-2). The methanol extract of plants S. sarmentosum and the major kaempferol glycosides from S. dendroideum have antinociceptive activity. It was noticed that anti-adipogenic activity of extracts from plants S. kamtschaticum were caused by inhibition of peroxisome-proliferator-activated receptor γ (PPARγ) expression and it’s dependent target genes, such as genes encoding adipocyte protein 2 (аР2), lipoprotein lipase (LPL), adiponectin and CD36. Polysaccharides fractions from S. telephium cause inhibition of cell adhesion of human fibroblast (MRC5) to laminin and fibronectin via interfere with integrin-mediated cell behaviour and they contributed to the role of polysaccharides in cell-matrix interaction. The methanol extract of plants S. sarmentosum exhibited a significant inhibitory activity in the chick embryo chorioallantoic membrane angiogenesis in a dose-dependent manner. The crude alkaloid fraction of S. sarmentosum caused a dose-dependent inhibition of cell proliferation on murine hepatoma cell line BNL CL.2 and human hepatoma cell line HepG2 without necrosis or apoptosis. Alkaloids from plants S. sarmentosum may improve survival of hepatoma patients via the inhibition of excessive growth of tumor cells. Plant’s juices have antiviral activity (S. sarmentosum, S. spurium, S. stahlii). Crude ethanol extract S. praealtum have spermicidal activity of the in mice and a relevant inhibitory effect of aqueous extract on human spermatozoa motility as well as an anti-fertilizing activity in rats. Hepatoprotective triterpenes, e.g., δ-amyrone, 3-epi-δ-amyrin, δ-amyrin and sarmentolin were isolated from S. sarmentosum. 2- and 2,6-substituted piperidine alkaloids (e.g., norsedamine, allosedridine, sedamine, allosedamine) are observed in plants S. acre, which in the presence of data on the use of pyridine and piperidine derivatives for treating neurodegenerative diseases (e.g., Alzheimer's disease), points on the promising research in this area. Taking into account that biologically active compounds are accumulated in the aboveground vegetative organs of plants of Sedum, the prospects of further study of the use of Sedum for the purposes of biotechnology and in the pharmaceutical industry becomes apparent. This work extends the existing views regarding the use of plants Sedum.

scholarly journals P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

2009 ◽  
Vol 29 (6) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leon M Tai ◽  
A Jane Loughlin ◽  
David K Male ◽  
Ignacio A Romero
Keyword(s):  
Breast Cancer ◽  
Human Brain ◽  
Breast Cancer Resistance Protein ◽  
Amyloid Β ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

Human MutT Homolog 1 (MTH1) Inhibitor Reduces the Biological Activity of Ovarian Carcinoma Cells

2022 ◽  
Vol 12 (5) ◽  
pp. 907-913
Author(s):  
Liyan Zhong ◽  
Yi Yi ◽  
Qian Liu ◽  
Yan Peng
Keyword(s):  
Biological Activity ◽  
Ovarian Carcinoma ◽  
Biological Activities ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Ovarian Carcinoma Cells ◽  
Proliferative Rate ◽  
Skov3 Cells ◽  
Significant Difference ◽  
Dose Dependent

This study intends to discuss the mechanism of MTH1 inhibitor (TH588) in the biological activity of ovarian carcinoma cells. A2780 and SKOV-3 cells were treated with different concentrations of TH588 and assigned into AT group (control), BT group (8 μmol/L TH588), CT group (16 μmol/L), DT group (32 μmol/L), ET group (64 μmol/L) and FT group (128 μmol/L) followed by measuring level of Bcl-2 and Bax by Western blot and PCR, and cell biological activities by MTT, FCM and Transwell chamber assay. The cell proliferative rate was not affected in AT group, but was lower in other groups in a reverse dose-dependent manner. There was significant difference on apoptotic rate and cell invasion among groups with increased apoptosis and reduce invasion after TH588 treatment. FT group showed lowest expression of Bcl-2 and Bax compared to other groups. In conclusion, the biological activity of A2780/SKOV3 cells could be reduced by MTH1 inhibitor which was probably through regulation of Bax and Bcl-2 expression.

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