scholarly journals The Multidrug Resistance-Reversing Activity of a Novel Antimicrobial Peptide

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1963
Author(s):  
Qiu-Xu Teng ◽  
Xiaofang Luo ◽  
Zi-Ning Lei ◽  
Jing-Quan Wang ◽  
John Wurpel ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Antimicrobial Peptides ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Abc Transporters ◽  
Intracellular Accumulation ◽  
The Past ◽  
Novel Strategy ◽  
New Generation ◽  
Abcb1 Transporter

The overexpression of ATP-binding cassette (ABC) transporters is a common cause of multidrug resistance (MDR) in cancers. The intracellular drug concentration of cancer cells can be decreased relative to their normal cell counterparts due to increased expression of ABC transporters acting as efflux pumps of anticancer drugs. Over the past decades, antimicrobial peptides have been investigated as a new generation of anticancer drugs and some of them were reported to have interactions with ABC transporters. In this article, we investigated several novel antimicrobial peptides to see if they could sensitize ABCB1-overexpressing cells to the anticancer drugs paclitaxel and doxorubicin, which are transported by ABCB1. It was found that peptide XH-14C increased the intracellular accumulation of ABCB1 substrate paclitaxel, which demonstrated that XH-14C could reverse ABCB1-mediated MDR. Furthermore, XH-14C could stimulate the ATPase activity of ABCB1 and the molecular dynamic simulation revealed a stable binding pose of XH-14C-ABCB1 complex. There was no change on the expression level or the location of ABCB1 transporter with the treatment of XH-14C. Our results suggest that XH-14C in combination with conventional anticancer agents could be used as a novel strategy for cancer treatment.

Recent Progress on Apoptotic Activity of Triazoles

2021 ◽  
Vol 22 ◽  
Author(s):  
Pelin Çıkla-Süzgün ◽  
Ş. Güniz Küçükgüzel
Keyword(s):  
Cancer Progression ◽  
Anticancer Agents ◽  
Heterocyclic Compounds ◽  
Rational Design ◽  
Vital Role ◽  
Anticancer Activities ◽  
The Past ◽  
Small Molecule Drugs ◽  
Apoptotic Activity ◽  
New Generation

Abstract: Apoptosis, often called programmed cell death, is a self-directed cell destruction process. It differs from classical necrosis by activation of caspases. Apoptosis is directly related to cancer progression and plays a vital role in carcinogenesis. All cytotoxic drugs and radiation therapy programs initiates apoptosis in tumor cells. Today, studies show that heterocyclic compounds that contain triazole funtionality have anticancer activities. Triazoles are 5-membered rings, which contain two carbon and three nitrogen atoms Therefore, many researchers have synthesized these small active compounds as target structures and evaluated their apoptotic activities. The present review describs more recent medicinal aspects of triazoles as anticancer agents reported during the past few years. We hope that the bioactivity of triazole derivatives will be beneficial for the rational design of new generation of small molecule drugs.

Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo

2015 ◽  
Vol 93 (1) ◽  
pp. 33-38 ◽  
Author(s):  
Tianxiao Zhao ◽  
Yun Song ◽  
Baomin Liu ◽  
Qianqian Qiu ◽  
Lei Jiao ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Anticancer Agents ◽  
Efflux Pump ◽  
Therapeutic Index ◽  
Intracellular Accumulation ◽  
P Glycoprotein ◽  
Reversal Mechanism

The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L−1) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.

scholarly journals Tetrandrine Interaction with ABCB1 Reverses Multidrug Resistance in Cancer Cells Through Competition with Anti-Cancer Drugs Followed by Downregulation of ABCB1 Expression

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4383 ◽  
Author(s):  
Dan Liao ◽  
Wei Zhang ◽  
Pranav Gupta ◽  
Zi-Ning Lei ◽  
Jing-Quan Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cellular Localization ◽  
Treatment Time ◽  
Mrna Level ◽  
Chemotherapeutic Agents ◽  
Mdr1 Gene ◽  
P Glycoprotein ◽  
Abcb1 Transporter

The overexpression of ABC transporters induced by anticancer drugs has been found to be the main cause of multidrug resistance. It is actually also a strategy by which cancer cells escape being killed. Tetrandrine is a natural product extracted from the stem of Tinospora crispa. In this study, tetrandrine showed synergistic cytotoxic activity in combinational use with chemotherapeutic drugs, such as Doxorubicin, Vincristine, and Paclitaxel, in both drug-induced and MDR1 gene-transfected cancer cells that over-expressed ABCB1/P-glycoprotein. Tetrandrine stimulated P-glycoprotein ATPase activity, decreased the efflux of [3H]-Paclitaxel and increased the intracellular accumulation of [3H]-Paclitaxel in KB-C2 cells. Furthermore, SW620/Ad300 and KB-C2 cells pretreated with 1 μM tetrandrine for 72 h decreased P-glycoprotein expression without changing its cellular localization. This was demonstrated through Western blotting and immunofluorescence analysis. Interestingly, down-regulation of P-glycoprotein expression was not correlated with gene transcription, as the MDR1 mRNA level exhibited a slight fluctuation in SW620/Ad300 and KB-C2 cells at 0, 24, 48, and 72 h treatment time points. In addition, molecular docking analysis predicted that tetrandrine had inhibitory potential with the ABCB1 transporter. Our results suggested that tetrandrine can antagonize MDR in both drug-selected and MDR1 gene-transfected cancer cells by down regulating the expression of the ABCB1 transporter, followed by increasing the intracellular concentration of chemotherapeutic agents. The combinational therapy using tetrandrine and other anticancer drugs could promote the treatment efficiency of drugs that are substrates of ABCB1.

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.

ABC transporters in the balance: is there a role in multidrug resistance?1

2005 ◽  
Vol 33 (1) ◽  
pp. 241-245 ◽  
Author(s):  
O. Polgar ◽  
S.E. Bates
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Anticancer Agents ◽  
Abc Transporters ◽  
Drug Accumulation ◽  
Critical Studies ◽  
Multidrug Transporters ◽  
Consequent Reduction ◽  
And Function

Drug resistance can occur at several levels and is the major cause of treatment failure in oncology. The ABC (ATP-binding cassette) transporters, beginning with the discovery of P-gylcoprotein (Pgp) almost 30 years ago, have been intensively studied as potential mediators of drug resistance. Although we understand that drug resistance is almost certainly multifactorial, investigators have attempted to link anticancer drug resistance to overexpression of ABC transporters and the consequent reduction in drug accumulation. A body of evidence implicated Pgp as being important in clinical outcome; however, critical studies aimed at proving the hypothesis using Pgp inhibitors in clinical trials have to date failed. Identification of the MRP (multidrug resistance protein)/ABCC subfamily expanded the possible mechanisms of reduced drug accumulation, and the discovery of ABCG2 added a new chapter in these investigations. Correlative studies examining ABCG2 and the ABCC subfamily members in clinical drug resistance have been less avidly pursued, while basic molecular studies of structure and function have proceeded briskly. Recently, studies have focused on how single nucleotide polymorphism in multidrug transporters might affect the pharmacokinetics and pharmacodynamics of anticancer agents. These studies suggest an important role for ABC transporters in pharmacology, independent of the ultimate determination of their role in multidrug resistance.

scholarly journals Flavonoid Dimers as Bivalent Modulators for Pentamidine and Sodium Stiboglucanate Resistance in Leishmania

2006 ◽  
Vol 51 (3) ◽  
pp. 930-940 ◽  
Author(s):  
Iris L. K. Wong ◽  
Kin-Fai Chan ◽  
Brendan A. Burkett ◽  
Yunzhe Zhao ◽  
Yi Chai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Ethylene Glycol ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Copy Number ◽  
Atp Binding ◽  
Sodium Stibogluconate ◽  
Intracellular Accumulation ◽  
Reversal Agent

ABSTRACT Drug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with ∼3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1 −/−, LeMDR1 +/+, and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania.

The Contribution of Intermediate-Voltage, High-Resolution Electron Microscopy In Materials Science: An Appraisal

1990 ◽  
Vol 48 (1) ◽  
pp. 478-479
Author(s):  
John L. Hutchison
Keyword(s):  
High Resolution ◽  
Materials Science ◽  
High Resolution Electron Microscopy ◽  
Optical Diffraction ◽  
The Past ◽  
Resolution Electron ◽  
Extreme Sensitivity ◽  
Electron Microscopes ◽  
New Generation ◽  
Small Metal Particles

Over the past five years or so the development of a new generation of high resolution electron microscopes operating routinely in the 300-400 kilovolt range has produced a dramatic increase in resolution, to around 1.6 Å for “structure resolution” and approaching 1.2 Å for information limits. With a large number of such instruments now in operation it is timely to assess their impact in the various areas of materials science where they are now being used. Are they falling short of the early expectations? Generally, the manufacturers’ claims regarding resolution are being met, but one unexpected factor which has emerged is the extreme sensitivity of these instruments to both floor-borne and acoustic vibrations. Successful measures to counteract these disturbances may require the use of special anti-vibration blocks, or even simple oil-filled dampers together with springs, with heavy curtaining around the microscope room to reduce noise levels. In assessing performance levels, optical diffraction analysis is becoming the accepted method, with rotational averaging useful for obtaining a good measure of information limits. It is worth noting here that microscope alignment becomes very critical for the highest resolution.In attempting an appraisal of the contributions of intermediate voltage HREMs to materials science we will outline a few of the areas where they are most widely used. These include semiconductors, oxides, and small metal particles, in addition to metals and minerals.

Molecular Epidemiology and Biomarkers in Etiologic Cancer Research: The New in Light of the Old

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Gene Expression ◽  
Cancer Research ◽  
Molecular Epidemiology ◽  
Exposure Assessment ◽  
Large Scale ◽  
First Generation ◽  
Cancer Epidemiology ◽  
Policy Changes ◽  
The Past ◽  
New Generation

The purpose of this review is to evaluate progress inmolecular epidemiology over the past 24 years in canceretiology and prevention to draw lessons for futureresearch incorporating the new generation of biomarkers.Molecular epidemiology was introduced inthe study of cancer in the early 1980s, with theexpectation that it would help overcome some majorlimitations of epidemiology and facilitate cancerprevention. The expectation was that biomarkerswould improve exposure assessment, document earlychanges preceding disease, and identify subgroupsin the population with greater susceptibility to cancer,thereby increasing the ability of epidemiologic studiesto identify causes and elucidate mechanisms incarcinogenesis. The first generation of biomarkers hasindeed contributed to our understanding of riskandsusceptibility related largely to genotoxic carcinogens.Consequently, interventions and policy changes havebeen mounted to reduce riskfrom several importantenvironmental carcinogens. Several new and promisingbiomarkers are now becoming available for epidemiologicstudies, thanks to the development of highthroughputtechnologies and theoretical advances inbiology. These include toxicogenomics, alterations ingene methylation and gene expression, proteomics, andmetabonomics, which allow large-scale studies, includingdiscovery-oriented as well as hypothesis-testinginvestigations. However, most of these newer biomarkershave not been adequately validated, and theirrole in the causal paradigm is not clear. There is a needfor their systematic validation using principles andcriteria established over the past several decades inmolecular cancer epidemiology.

Vēsturiskā atmiņa Latvijas teātra jaunās paaudzes mākslinieku darbos: izrādes „Dvēseļu utenis” piemērs

2020 ◽  
pp. 269-275
Author(s):  
Ieva Rodiņa
Keyword(s):  
Historical Memory ◽  
Intergenerational Relationships ◽  
Phenomenological Approach ◽  
Political Theater ◽  
Hermeneutic Phenomenological ◽  
The Past ◽  
The Social ◽  
Humanistic Study ◽  
New Generation ◽  
Flea Market

The aim of the research “Historical Memory in the Works of the New Generation of Latvian Theater Artists: The Example of “The Flea Market of the Souls” is to focus on the current but at the same time little discussed topic in Latvian theater – the change of generations and the social processes connected to it, that are expressed on the level of world views, experiences, intergenerational relationships. Most directly, these changes are reflected in the phenomenon of historical memory. The concept of “postmemory” was defined by German professor Marianne Hirsch in 1992, suggesting that future generations are closely related to the personal and collective cultural traumas of previous generations, which are passing on the past experience through historical memory, thus affecting the present. Grotesque, self-irony, and focusing on socio-political, provocative questions and themes are the connecting point of the generation of young Latvian playwrights born in the late 1980s and early 1990s, including such personalities as Jānis Balodis, Rasa Bugavičute-Pēce, Matīss Gricmanis, Justīne Kļava, etc. However, unlike Matīss Gricmanis or Janis Balodis who represent the aesthetics of political theater, in Justīne Kļava’s works, sociopolitical processes become the background of a generally humanistic study of the relationships between generations. This theme is represented not only in “The Flea Market of the Souls”, but also in other plays, like “Jubilee ‘98” and “Club “Paradise””. The tendency to investigate the traces left by the Soviet heritage allows to define these works as autobiographical researches of the identity of the post-Soviet generation, analyzing life in today's Latvia in terms of historical memory. Using the semiotic, hermeneutic, phenomenological approach, the play “The Flea Market of the Souls” and its production in Dirty Deal Teatro (2017) are analyzed as one of the most vivid works reflecting the phenomenon of historical memory in recent Latvian original drama.

Recent Design and Structure-Activity Relationship Studies on Modifications of DHFR Inhibitors as Anticancer Agents

2019 ◽  
Vol 26 ◽  
Author(s):  
Agnieszka Wróbel ◽  
Danuta Drozdowska
Keyword(s):  
Anticancer Activity ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Physicochemical Characterization ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Biological Research ◽  
Structure Activity ◽  
Dhfr Inhibitors

Background: Dihydrofolate reductase (DHFR) has been known for decades as a molecular target for antibacterial, antifungal and anti-malarial treatments. This enzyme is becoming increasingly important in the design of new anticancer drugs, which is confirmed by numerous studies including modelling, synthesis and in vitro biological research. This review aims to present and discuss some remarkable recent advances on the research of new DHFR inhibitors with potential anticancer activity. Methods: The scientific literature of the last decade on the different types of DHFR inhibitors has been searched. The studies on design, synthesis and investigation structure-activity relationship were summarized and divided into several subsections depending on the leading molecule and its structural modification. Various methods of synthesis, potential anticancer activity and possible practical applications as DHFR inhibitors of new chemical compounds were described and discussed. <p> Results: This review presents the current state of knowledge on the modification of known DHFR inhibitors and the structures and searching for over eighty new molecules, designed as potential anticancer drugs. In addition, DHFR inhibitors acting on thymidylate synthase (TS), carbon anhydrase (CA) and even DNA-binding are presented in this paper. <p> Conclusion: Thorough physicochemical characterization and biological investigations it is possible to understand structure-activity relationship of DHFR inhibitors. This will enable even better design and synthesis of active compounds, which would have the expected mechanism of action and the desired activity.

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