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 Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur

2018 ◽  
Vol 4 (5) ◽  
pp. 397-407 ◽  
Author(s):  
Awais Anwar ◽  
Emma Gould ◽  
Ryan Tinson ◽  
Javaid Iqbal ◽  
Chris Hamilton
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Potential ◽  
Antimicrobial Properties ◽  
Molecular Targets ◽  
Cancer Cell Lines ◽  
Special Focus ◽  
Anticancer Activities ◽  
Comprehensive Overview ◽  
Anticancer Properties

Abstract Purpose of review This article provides a brief overview of natural phytoprotective products of allium with a special focus on the therapeutic potential of diallyl polysulfanes from garlic, their molecular targets and their fate in the living organisms. A comprehensive overview of antimicrobial and anticancer properties of published literature is presented for the reader to understand the effective concentrations of polysulfanes and their sensitivity towards different human pathogenic microbes, fungi, and cancer cell lines. Recent findings The article finds polysulfanes potentials as new generation novel antibiotics and chemo preventive agent. The effective dose rates of polysulfanes for antimicrobial properties are in the range of 0.5–40 mg/L and for anticancer 20–100 μM. The molecular targets for these redox modulators are mainly cellular thiols as well as inhibition and/or activation of certain cellular proteins in cancer cell lines. Summary Antimicrobial and anticancer activities of polysulfanes published in the literature indicate that with further development, they could be promising candidates for cancer prevention due to their selectivity towards abnormal cells.

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.

scholarly journals ID3007 Mechanisms underlying the anticancer activities of the selected phytochemicals and their therapeutic implication in AGS gastric cancer cells

2017 ◽  
Vol 4 (S) ◽  
pp. 19
Author(s):  
Somi Kim Cho
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Synergistic Effects ◽  
Mitotic Catastrophe ◽  
Cancer Drug ◽  
Histone Deacetylase 6 ◽  
Anticancer Activities ◽  
Gastric Cancer Cells ◽  
Ags Cells ◽  
High Concentrations

The cysteine-rich angiogenic inducer 61 (CYR61), an extracellular matrix-associated protein, is involved in survival, tumorigenesis, and drug resistance. There is an increasing demand for developing agents that target CYR61. Hence, we study the effects of flavones against CYR61-overexpressing human gastric adenocarcinoma AGS (AGS-cyr61) cells. Among the various flavones, quercetin had lowest IC50 value and reduced the viability of AGS-cyr61 cells even greater than that of AGS cells. Quercetin (1) down-regulates CYR61 and concomitantly decreases in the levels of MRP1 (multidrug resistance-associated protein 1) and nuclear factor NF-kappa B (κB) p65 subunit, (2) reverses multidrug resistance, and (3) inhibits colony formation in AGS-cyr61 cells. AGS-cyr61 cells treated with quercetin at sub IC50 over a range of 5-FU or ADR concentrations manifested strong synergistic effects with these two drugs. Our results demonstrate that CYR61 is a potential regulator of ABC transporters and quercetin can be the novel agent that improves the efficacy of anticancer drugs by down-regulating CYR61 and ABC transporters. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme which contributes to malignant progression in various cancer. Such effect on cancer brings more interest on developing HDAC6 inhibitors. Here, we found that compound D inhibits HDAC6 activity, increases acetylated α-tubulin, reduces the level of β-catenin, and suppresses cell proliferation. Increase of α-tubulin acetylation by compound D resulted in tubulin polymerization, and consequently, induced aberrant mitosis. Moreover, DTBP elicits different effects depending on different concentrations.   Treatment with high concentrations of compound D induces cell death by mitotic catastrophe, whereas low concentration of compound D induces senescence with upregulation of p21 and Rb, and increase in the phosphorylation of mTOR and the β-galactosidase activity. Therefore, compound D can also be considered as a promising new candidate for anti-cancer drug development.

scholarly journals Improved Anticancer Activities of a New Pentafluorothio-Substituted Vorinostat-Type Histone Deacetylase Inhibitor

2021 ◽  
Vol 14 (12) ◽  
pp. 1319
Author(s):  
Nils Goehringer ◽  
Yayi Peng ◽  
Bianca Nitzsche ◽  
Hannah Biermann ◽  
Rohan Pradhan ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Histone Deacetylases ◽  
Parent Compound ◽  
Hdac Inhibitors ◽  
Drug Candidate ◽  
Anticancer Activities ◽  
Drug Candidates ◽  
Anticancer Properties ◽  
Ic50 Values ◽  
Potent Drug

The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising epigenetic anticancer drugs and new HDAC inhibitors are sought for in order to obtain potent drug candidates. The new HDAC inhibitor SF5-SAHA was synthesized and analyzed for its anticancer properties. The new compound SF5-SAHA showed strong inhibition of tumor cell growth with IC50 values similar to or lower than that of the clinically applied reference compound vorinostat/SAHA (suberoylanilide hydroxamic acid). Target specific HDAC inhibition was demonstrated by Western blot analyses. Unspecific cytotoxic effects were not observed in LDH-release measurements. Pro-apoptotic formation of reactive oxygen species (ROS) and caspase-3 activity induction in prostate carcinoma and hepatocellular carcinoma cell lines DU145 and Hep-G2 seem to be further aspects of the mode of action. Antiangiogenic activity of SF5-SAHA was observed on chorioallantoic membranes of fertilized chicken eggs (CAM assay). The presence of the pentafluorothio-substituent of SF5-SAHA increased the antiproliferative effects in both solid tumor and leukemia/lymphoma cell models when compared with its parent compound vorinostat. Based on this preliminary study, SF5-SAHA has the prerequisites to be further developed as a new HDAC inhibitory anticancer drug candidate.

scholarly journals The Aquaporin-3-Inhibiting Potential of Polyoxotungstates

2020 ◽  
Vol 21 (7) ◽  
pp. 2467 ◽  
Author(s):  
Catarina Pimpão ◽  
Inês V. da Silva ◽  
Andreia F. Mósca ◽  
Jacinta O. Pinho ◽  
Maria Manuela Gaspar ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Growth ◽  
Anticancer Drugs ◽  
Inhibitory Concentration ◽  
Yeast Cells ◽  
Anticancer Activities ◽  
Cancer Cell Growth ◽  
Aquaporin 3 ◽  
Anticancer Properties ◽  
First Time

Polyoxometalates (POMs) are of increasing interest due to their proven anticancer activities. Aquaporins (AQPs) were found to be overexpressed in tumors bringing particular attention to their inhibitors as anticancer drugs. Herein, we report for the first time the ability of polyoxotungstates (POTs), such as of Wells–Dawson P2W18, P2W12, and P2W15, and Preyssler P5W30 structures, to affect aquaporin-3 (AQP3) activity and impair melanoma cell migration. The tested POTs were revealed to inhibit AQP3 function with different effects, with P2W18, P2W12, and P5W30 being the most potent (50% inhibitory concentration (IC50) = 0.8, 2.8, and 3.2 µM), and P2W15 being the weakest (IC50 > 100 µM). The selectivity of P2W18 toward AQP3 was confirmed in yeast cells transformed with human aquaglyceroporins. The effect of P2W12 and P2W18 on melanoma cells that highly express AQP3 revealed an impairment of cell migration between 55% and 65% after 24 h, indicating that the anticancer properties of these compounds may in part be due to the blockage of AQP3-mediated permeability. Altogether, our data revealed that P2W18 strongly affects AQP3 activity and cancer cell growth, unveiling its potential as an anticancer drug against tumors where AQP3 is highly expressed.

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 Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1756 ◽  
Author(s):  
Claudia Ceci ◽  
Pedro Lacal ◽  
Lucio Tentori ◽  
Maria De Martino ◽  
Roberto Miano ◽  
...  
Keyword(s):  
Experimental Evidence ◽  
Ellagic Acid ◽  
Therapeutic Potential ◽  
Supportive Therapy ◽  
Anticancer Properties ◽  
Metastatic Process ◽  
Apoptotic Effects ◽  
Near Future

Ellagic acid (EA) is a naturally occurring polyphenolic compound endowed with strong antioxidant and anticancer properties that is present in high quantity in a variety of berries, pomegranates, and dried fruits. The antitumor activity of EA has been mostly attributed to direct antiproliferative and apoptotic effects. Moreover, EA can inhibit tumour cell migration, extra-cellular matrix invasion and angiogenesis, all processes that are crucial for tumour infiltrative behaviour and the metastatic process. In addition, EA may increase tumour sensitivity to chemotherapy and radiotherapy. The aim of this review is to summarize the in vitro and in vivo experimental evidence supporting the anticancer activity of pure EA, its metabolites, and EA-containing fruit juice or extracts in a variety of solid tumour models. The EA oral administration as supportive therapy to standard chemotherapy has been recently evaluated in small clinical studies with colorectal or prostate cancer patients. Novel formulations with improved solubility and bioavailability are expected to fully develop the therapeutic potential of EA derivatives in the near future.

scholarly journals Characterization of Tachyplesin Peptides and Their Cyclized Analogues to Improve Antimicrobial and Anticancer Properties

2019 ◽  
Vol 20 (17) ◽  
pp. 4184 ◽  
Author(s):  
Felicitas Vernen ◽  
Peta J. Harvey ◽  
Susana A. Dias ◽  
Ana Salomé Veiga ◽  
Yen-Hua Huang ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Lipid Membranes ◽  
Therapeutic Potential ◽  
Lipid Binding ◽  
Anticancer Activities ◽  
Host Defense Peptides ◽  
Anticancer Properties ◽  
Human Red Blood Cells ◽  
Backbone Cyclization ◽  
Reduced Toxicity

Tachyplesin I, II and III are host defense peptides from horseshoe crab species with antimicrobial and anticancer activities. They have an amphipathic β-hairpin structure, are highly positively-charged and differ by only one or two amino acid residues. In this study, we compared the structure and activity of the three tachyplesin peptides alongside their backbone cyclized analogues. We assessed the peptide structures using nuclear magnetic resonance (NMR) spectroscopy, then compared the activity against bacteria (both in the planktonic and biofilm forms) and a panel of cancerous cells. The importance of peptide-lipid interactions was examined using surface plasmon resonance and fluorescence spectroscopy methodologies. Our studies showed that tachyplesin peptides and their cyclic analogues were most potent against Gram-negative bacteria and melanoma cell lines, and showed a preference for binding to negatively-charged lipid membranes. Backbone cyclization did not improve potency, but improved peptide stability in human serum and reduced toxicity toward human red blood cells. Peptide-lipid binding affinity, orientation within the membrane, and ability to disrupt lipid bilayers differed between the cyclized peptide and the parent counterpart. We show that tachyplesin peptides and cyclized analogues have similarly potent antimicrobial and anticancer properties, but that backbone cyclization improves their stability and therapeutic potential.

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.

ABC Transporters: Regulation and Association with Multidrug Resistance in Hepatocellular Carcinoma and Colorectal Carcinoma

2019 ◽  
Vol 26 (7) ◽  
pp. 1224-1250 ◽  
Author(s):  
María Paula Ceballos ◽  
Juan Pablo Rigalli ◽  
Lucila Inés Ceré ◽  
Mariana Semeniuk ◽  
Viviana Alicia Catania ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multidrug Resistance ◽  
Colorectal Carcinoma ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Future Directions ◽  
Associated Proteins ◽  
Post Transcriptional Regulation

:For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells.:This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.

Sign in / Sign up

Export Citation Format

Share Document