scholarly journals Inhibitors of N-glycosylation as a potential tool for analysis of the mechanism of action and cellular localisation of glycoprotein P.

2012 ◽  
Vol 59 (4) ◽  
Author(s):  
Karolina Wojtowicz ◽  
Witold Szaflarski ◽  
Radosław Januchowski ◽  
Piotr Zawierucha ◽  
Michał Nowicki ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Membrane Protein ◽  
Mechanism Of Action ◽  
Therapeutic Potential ◽  
Basic Knowledge ◽  
Glycoprotein P ◽  
Intracellular Location ◽  
Cellular Localisation ◽  
Modified Proteins ◽  
Potential Tool

Multidrug resistance has for many years attracted attention of numerous investigators. Attempts have also been made to increase efficiency of anti-neoplastic therapy. For this reason, most of efforts have been devoted to analysing proteins engaged in the mechanism of multidrug resistance such as the N-glycosylated membrane protein glycoprotein P. Interestingly, glycosylation probably plays a significant role in the intracellular location and activity of modified proteins. Inhibitors of glycosylation have been demonstrated to alter the activity of glycoprotein P in various ways, depending on the cell line examined. These inhibitors markedly reduce multidrug resistance of cancer cells, thus promoting success of anti-neoplastic therapy. Here, we review the basic knowledge on N-glycosylation inhibitors, their effect on glycoprotein P and their therapeutic potential.

scholarly journals Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 458
Author(s):  
Sabesan Yoganathan ◽  
Anushan Alagaratnam ◽  
Nikita Acharekar ◽  
Jing Kong
Keyword(s):  
Multidrug Resistance ◽  
Small Molecules ◽  
Anticancer Drugs ◽  
Abc Transporters ◽  
Ellagic Acid ◽  
Therapeutic Potential ◽  
Anticancer Activities ◽  
Glycoprotein P ◽  
Major Mechanism ◽  
Anticancer Properties

Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Although multiple generations of P-gp inhibitors have been identified to date, reported compounds have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have emerged as a promising class of compounds to address P-gp linked MDR. This review highlights the chemical structure and anticancer activities of selected members of a structurally unique class of ‘biaryl’ polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced into these natural products for medicinal chemistry studies is also provided.

scholarly journals 5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1839
Author(s):  
Omolbanin Shahraki ◽  
Mehdi Khoshneviszadeh ◽  
Mojtaba Dehghani ◽  
Maryam Mohabbati ◽  
Marjan Tavakkoli ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Therapeutic Potential ◽  
Uterine Sarcoma ◽  
Glycoprotein P ◽  
Hek 293 ◽  
Reversal Agents ◽  
Flow Cytometric Method ◽  
Flow Cytometric ◽  
Induced Apoptosis ◽  
Cancerous Cells

Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2 with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.

From Ocean to Bedside: the Therapeutic Potential of Molluscan Hemocyanins

2018 ◽  
Vol 25 (20) ◽  
pp. 2292-2303 ◽  
Author(s):  
Negar Talaei Zanjani ◽  
Monica Miranda Saksena ◽  
Fariba Dehghani ◽  
Anthony L. Cunningham
Keyword(s):  
Antiviral Activity ◽  
Clinical Efficacy ◽  
Mechanism Of Action ◽  
Therapeutic Agent ◽  
Marine Invertebrates ◽  
Therapeutic Potential ◽  
Biological Functions ◽  
Anticancer Properties ◽  
Mechanistic Understanding

Hemocyanins are large and versatile glycoproteins performing various immunological and biological functions in many marine invertebrates including arthropods and molluscs. This review discusses the various pharmacological applications of mollusc hemocyanin such as antiviral activity, immunostimulatory and anticancer properties that have been reported in the literature between the years 2000 and 2016. Emphasis is placed on a better mechanistic understanding of hemocyanin as a therapeutic agent. Elucidation of the mechanism of action is essential to improve the clinical efficacy and for a better understanding of some endogenous immunological functions of this complex glycoprotein.

scholarly journals Balneotherapy with the Use of Radon–Sulphide Water: The Mechanisms of Therapeutic Effect

2021 ◽  
Vol 11 (6) ◽  
pp. 2849
Author(s):  
Lilla Pawlik-Sobecka ◽  
Joanna Górka-Dynysiewicz ◽  
Jadwiga Kuciel-Lewandowska
Keyword(s):  
Natural Resources ◽  
Therapeutic Effect ◽  
Mechanism Of Action ◽  
World Literature ◽  
Therapeutic Potential ◽  
Health Resort ◽  
The World ◽  
Spa Treatment ◽  
Combined Action

Despite its enormous therapeutic potential, spa treatment is not always properly perceived, hence the numerous attempts to assess its effectiveness. In the world literature, there are few reports on therapy using sulphur- and radon-containing therapeutic waters. In countries with a long tradition of balneotherapy, activity in this field of medicine is evident. Undoubtedly, the interest in balneotherapy results also from natural resources used in spa medicine, which, as geological and balneochemical research shows, are enormous in Poland. A particular example of the occurrence of radon–sulphide waters, rare on the European scale, is the Przerzeczyn-Zdrój health resort. The mechanism of action of therapeutic waters is not fully explored, but their effectiveness in therapy is confirmed by many authors. It is believed to be an effect of combined action of many factors, the most important of which are thermal, mechanical, and chemical.

scholarly journals Selective Cytotoxicity of Piperine over Multidrug Resistance Leukemic Cells

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 934
Author(s):  
Julia Quarti ◽  
Daianne N. M. Torres ◽  
Erika Ferreira ◽  
Raphael S. Vidal ◽  
Fabiana Casanova ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Black Pepper ◽  
Leukemic Cells ◽  
Glycoprotein P ◽  
Cytotoxic Effects ◽  
Collateral Sensitivity ◽  
Main Challenge ◽  
Independent Mechanism ◽  
High Level ◽  
Parp 1

Multidrug resistance (MDR) is the main challenge in the treatment of chronic myeloid leukemia (CML), and P-glycoprotein (P-gp) overexpression is an important mechanism involved in this resistance process. However, some compounds can selectively affect MDR cells, inducing collateral sensitivity (CS), which may be dependent on P-gp. The aim of this study was to investigate the effect of piperine, a phytochemical from black pepper, on CS induction in CML MDR cells, and the mechanisms involved. The results indicate that piperine induced CS, being more cytotoxic to K562-derived MDR cells (Lucena-1 and FEPS) than to K562, the parental CML cell. CS was confirmed by analysis of cell metabolic activity and viability, cell morphology and apoptosis. P-gp was partially required for CS induction. To investigate a P-gp independent mechanism, we analyzed the possibility that poly (ADP-ribose) polymerase-1 (PARP-1) could be involved in piperine cytotoxic effects. It was previously shown that only MDR FEPS cells present a high level of 24 kDa fragment of PARP-1, which could protect these cells against cell death. In the present study, piperine was able to decrease the 24 kDa fragment of PARP-1 in MDR FEPS cells. We conclude that piperine targets selectively MDR cells, inducing CS, through a mechanism that might be dependent or not on P-gp.

scholarly journals Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

2019 ◽  
Vol 442 ◽  
pp. 91-103 ◽  
Author(s):  
Albert A. De Vera ◽  
Pranav Gupta ◽  
Zining Lei ◽  
Dan Liao ◽  
Silpa Narayanan ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein

scholarly journals Extract from Dioscorea bulbifera L. rhizomes aggravate pirarubicin-induced cardiotoxicity by inhibiting the expression of P-glycoprotein and multidrug resistance-associated protein 2 in the mouse liver

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Li-rui Sun ◽  
Qiu-shi Guo ◽  
Wei Zhou ◽  
Min Li
Keyword(s):  
Multidrug Resistance ◽  
Mouse Liver ◽  
Adverse Reactions ◽  
Heart Tissue ◽  
Efflux Transporters ◽  
Glycoprotein P ◽  
Chinese Herbal ◽  
Good Safety Profile ◽  
P Glycoprotein ◽  
Dioscorea Bulbifera

AbstractChinese herbal medicine is widely used because it has a good safety profile and few side effects. However, the risk of adverse drug reactions caused by herb-drug interactions (HDIs) is often overlooked. Therefore, the task of identifying possible HDIs and elucidating their mechanisms is of great significance for the prevention and treatment of HDI-related adverse reactions. Since extract from Dioscorea bulbifera L. rhizomes (DB) can cause various degrees of liver damage, it is speculated that HDIs may occur between DB extract and chemicals metabolized or excreted by the liver. Our study revealed that the cardiotoxicity of pirarubicin (THP) was increased by co-administration of DB, and the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in the liver was inhibited by DB extract, which led to the accumulation of THP in heart tissue. In conclusion, there are risks of the co-administration of DB extract and THP. The mechanism of HDIs can be better revealed by targeting the efflux transporters.

Potential therapy of Sambiloto plant (Andrographis paniculata) using multi-compounds analysis

2021 ◽  
Vol 129 (4) ◽  
Author(s):  
Handayani ◽  
Wiwik Winarningsih
Keyword(s):  
Herbal Medicine ◽  
Receptor Antagonist ◽  
Mechanism Of Action ◽  
Receptor Agonist ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Andrographis Paniculata ◽  
Chemical Bonds ◽  
Receptor Kinase ◽  
Active Content

Introduction: Sambiloto plant (Andrographis paniculata) is often used as herbal medicine plant in Indonesia. Previous evidence indicates the use of a whole plant or single-compound approach. Analysis of multi-compounds is needed to determine the therapeutic potential for standardizing herbal medicine to provide a reliable effect. Methods: An exploratory study searching for the active content of A. paniculata was carried out in the Knapsack program. The chemical structure is analyzed computationally using Prediction of Activity Spectra for Substances (PASS) software. The analysis of the mechanism of action of drug molecules was analyzed using the Search Tool for Interacting Chemicals (STITCH) software. Results: The active content of A. paniculata is 46 types, with 5 of them having 6 effects based on chemical bonds and targeting 12 receptor proteins. Five active contents of A. paniculata include andrographidin A, caffeic acid, chlorogenic acid, wogonin 5-glucoside, and cinnamic acid. Analysis of the mechanism of action of A. paniculata based on 12 target proteins from active ingredients using a multi-compound approach shows 6 unique biological processes. Based on the chemical bonds, 5 active contents of A. paniculata have six effects, including anaphylatoxin receptor antagonist, a beta-adrenergic receptor kinase inhibitor, GABA C receptor agonist, G-protein-coupled receptor kinase inhibitor, Aryl hydrocarbon receptor agonist, and Nicotinic alpha6beta3beta4alpha5 receptor antagonist. Conclusion: There is a therapeutic potential of A. paniculata with multi-compounds analysis. A molecular docking analysis is needed to predict the affinity between the ligand (active ingredient) and the target protein.

Expression of hamster P-glycoprotein and multidrug resistance in DNA-mediated transformants of mouse LTA cells

1987 ◽  
Vol 7 (2) ◽  
pp. 718-724
Author(s):  
K L Deuchars ◽  
R P Du ◽  
M Naik ◽  
D Evernden-Porelle ◽  
N Kartner ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dna Sequences ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Recipient Mouse ◽  
Strongly Correlated ◽  
Wild Type ◽  
Glycoprotein P ◽  
Single Drug ◽  
P Glycoprotein

The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.

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