Chalcones as Promising Antitumor Agents by Targeting the p53 Pathway: An Overview and New Insights in Drug-Likeness

The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53–MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53–MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.

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The Δ133p53 Isoforms, Tuners of the p53 Pathway

Cancers ◽

10.3390/cancers12113422 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3422

Author(s):

Sebastien M. Joruiz ◽

Jessica A. Beck ◽

Izumi Horikawa ◽

Curtis C. Harris

Keyword(s):

Cell Fate ◽

Current Knowledge ◽

P53 Protein ◽

Tp53 Gene ◽

Premature Aging ◽

Protein Isoforms ◽

Cellular Functions ◽

P53 Pathway ◽

Transactivation Domains ◽

P53 Isoforms

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.

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Protease Inhibitory Effect of Natural Polyphenolic Compounds on SARS-CoV-2: An In Silico Study

Molecules ◽

10.3390/molecules25204604 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4604

Author(s):

Rajveer Singh ◽

Anupam Gautam ◽

Shivani Chandel ◽

Arijit Ghosh ◽

Dhritiman Dey ◽

...

Keyword(s):

In Silico ◽

Inhibitory Effect ◽

Polyphenolic Compounds ◽

Host Protein ◽

In Vivo Studies ◽

Pharmacokinetic Parameters ◽

Post Translational Modification ◽

In Silico Studies

The current pandemic, caused by SARS-CoV-2 virus, is a severe challenge for human health and the world economy. There is an urgent need for development of drugs that can manage this pandemic, as it has already infected 19 million people and led to the death of around 711,277 people worldwide. At this time, in-silico studies are providing lots of preliminary data about potential drugs, which can be a great help in further in-vitro and in-vivo studies. Here, we have selected three polyphenolic compounds, mangiferin, glucogallin, and phlorizin. These compounds are isolated from different natural sources but share structural similarities and have been reported for their antiviral activity. The objective of this study is to analyze and predict the anti-protease activity of these compounds on SARS-CoV-2main protease (Mpro) and TMPRSS2 protein. Both the viral protein and the host protein play an important role in the viral life cycle, such as post-translational modification and viral spike protein priming. This study has been performed by molecular docking of the compounds using PyRx with AutoDock Vina on the two aforementioned targets chosen for this study, i.e., SARS-CoV-2 Mpro and TMPRSS2. The compounds showed good binding affinity and are further analyzed by (Molecular dynamic) MD and Molecular Mechanics Poisson-Boltzmann Surface Area MM-PBSA study. The MD-simulation study has predicted that these natural compounds will have a great impact on the stabilization of the binding cavity of the Mpro of SARS-CoV-2. The predicted pharmacokinetic parameters also show that these compounds are expected to have good solubility and absorption properties. Further predictions for these compounds also showed no involvement in drug-drug interaction and no toxicity.

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Synthesis and Biological Evaluation of Novel Osthol Derivatives as Potent Cytotoxic Agents

Medicinal Chemistry ◽

10.2174/1573406414666180911161047 ◽

2019 ◽

Vol 15 (2) ◽

pp. 138-149

Author(s):

Saleem Farooq ◽

Javid A. Banday ◽

Aashiq Hussain ◽

Momina Nazir ◽

Mushtaq A. Qurishi ◽

...

Keyword(s):

Cancer Cells ◽

Natural Product ◽

Cancer Therapeutics ◽

Inhibitory Effect ◽

Biological Evaluation ◽

Negative Control ◽

Normal Breast ◽

Cytotoxic Agents ◽

Breast Epithelial Cell ◽

Exciting Field

Background: Natural product, osthol has been found to have important biological and pharmacological roles particularly having inhibitory effect on multiple types of cancer. Objective: The unmet needs in cancer therapeutics make its derivatization an important and exciting field of research. Keeping this in view, a whole new series of diverse analogues of osthol (1) were synthesized. Method: All the newly synthesized compounds were made through modification in the lactone ring as well as in the side chain of the osthol molecule and were subjected to anti-proliferative screening through 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) against four different human cancers of diverse origins viz. Colon (Colo-205), lung (A549), Leukemia (THP- 1) and breast (MCF-7) including SV40 transformed normal breast epithelial cell (fR-2). Results: Interestingly, among the tested molecules, most of the analogs displayed better antiproliferative activity than the parent Osthol 1. However, among all the tested analogs, compound 28 exhibited the best results against leukemia (THP1) cell line with IC50 of 5µM.Compound 28 induced potent apoptotic effects and G1 phase arrest in leukemia cancer cells (THP1). The population of apoptotic cells increased from 13.8% in negative control to 26.9% at 8μM concentration of 28. Compound 28 also induced a remarkable decrease in mitochondrial membrane potential (ΛΨm) leading to apoptosis of the cancer cells. Conclusion: A novel series of molecules derived from natural product osthol were synthesized, wherein compound 28 was found to be most effective against leukemia and with 10 fold less toxicity against normal cells. The compound induced cancer inhibition mainly through apoptosis and thus has a potential in cancer therapeutics.

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The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666200226112506 ◽

2020 ◽

Vol 15 (2) ◽

pp. 154-164 ◽

Cited By ~ 1

Author(s):

Ijaz Muhammad ◽

Noor Rahman ◽

Gul E. Nayab ◽

Sadaf Niaz ◽

Mohibullah Shah ◽

...

Keyword(s):

Molecular Docking ◽

Cancer Therapy ◽

Natural Product ◽

Signaling Pathway ◽

In Silico ◽

P53 Protein ◽

Dual Inhibitor ◽

P53 Signaling ◽

In Silico Studies ◽

P53 Signaling Pathway

Background: Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. Objective: In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. Methods: In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. Result: Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. Conclusion: Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.

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Breast Cancer Patient Prognosis Is Determined by the Interplay between TP53 Mutation and Alternative Transcript Expression: Insights from TP53 Long Amplicon Digital PCR Assays

Cancers ◽

10.3390/cancers13071531 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1531

Author(s):

Annette Lasham ◽

Nicholas Knowlton ◽

Sunali Y. Mehta ◽

Antony W. Braithwaite ◽

Cristin G. Print

Keyword(s):

Breast Cancer ◽

Gene Locus ◽

Tp53 Mutation ◽

P53 Protein ◽

Tp53 Gene ◽

Digital Pcr ◽

Protein Isoforms ◽

Alternative Transcript ◽

Transcript Expression ◽

Splice Sites

The TP53 gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight TP53 reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth TP53 reference transcript encoding ∆40p53α. We then applied these assays, alongside DNA sequencing of the TP53 gene locus, to tumors from a cohort of New Zealand (NZ) breast cancer patients. We found a high prevalence of mutations at TP53 splice sites in the NZ breast cancer cohort. Mutations at TP53 intron 4 splice sites were associated with overexpression of ∆133TP53 transcripts. Cox proportional hazards survival analysis showed that interplay between TP53 mutation status and expression of TP53 transcript variants was significantly associated with patient outcome, over and above standard clinical and pathological information. In particular, patients with no TP53 mutation and a low ratio of TP53 transcripts t2 to t1, which derive from alternative intron 1 acceptor splice sites, had a remarkably good outcome. We suggest that this type of analysis, integrating mutation and transcript expression, provides a step-change in our understanding of TP53 in cancer.

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Isolation of Disease-relevant p53 for Cryo-Electron Microscopy Analysis

10.21203/rs.3.pex-1294/v1 ◽

2021 ◽

Author(s):

Maria J. Solares ◽

GM Jonaid ◽

William Y. Luqiu ◽

Yanping Liang ◽

Madison C. Evans ◽

...

Keyword(s):

P53 Protein ◽

P53 Gene ◽

Tp53 Gene ◽

Tumor Suppressor Protein ◽

Protein Assemblies ◽

Cryo Electron Microscopy ◽

Naturally Occurring ◽

Imaging Protocols ◽

Electron Microscopy Analysis ◽

Microscopy Analysis

Abstract Tumor suppressor protein TP53 (p53) plays a multi-faceted role in all cells of thehuman body. Sadly, mutations in the TP53 gene are involved in nearly ~50% of tumors,spurring erratic cell growth and disease progression. Until recently, structural informationfor p53 remained incomplete and there are limited studies on native p53 produced inhuman tumors. Here, we present a highly reproducible and effective protocol to extract,enrich, and purify native p53 protein assemblies from cancer cells for downstreamstructural studies. This method does not introduce purification tags into the p53 gene andmaintains naturally occurring modifications. In conjunction with cryo-Electron Microscopytechniques, we determined new structures for p53 monomers (~50 kDa) and tetramers(~200 kDa) at spatial resolutions of ~4.8 Å and ~7 Å, respectively.1 These modelsrevealed new insights for flexible regions of p53 along with biologically-relevantubiquitination sites. Combining biochemical and structural imaging protocols, we aim tobuild a better understanding of native p53’s impact in cancer formation.

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Impact of p53 modulation on interactions between p53 family members during HaCaT keratinocytes differentiation

Bulletin of Russian State Medical University ◽

10.24075/brsmu.2020.082 ◽

2020 ◽

Author(s):

AL Rusanov ◽

PM Kozhin ◽

DD Romashin ◽

MN Karagyaur ◽

NG Luzgina

Keyword(s):

Cell Line ◽

P53 Protein ◽

Tp53 Gene ◽

Negative Regulator ◽

Elevated Concentration ◽

Hacat Cells ◽

Differentiation Markers ◽

Substantial Impact ◽

Skin Physiology

HaCaT cell line is a widely used model for studying normal human keratinocytes. However, mutations of TP53 gene are typical for this cell line, which have a substantial impact on functions of the encoded protein. The features of this regulatory circuit should be considered when using HaСaT cells for assessment of human skin physiology and pathology in vitro. The study was aimed to assess the features of differentiation realization in HaCaT cells with modulated activity of p53 protein. The expression of p53 was reduced by knockdown of TP53 gene by shRNA (by 2.2 times, p < 0.05), and the elevated concentration of the p53 active forms was achieved via exposure of cells to Nutlin-3a, the MDM2 inhibitor and the major negative regulator of p53. It has been found that regulation of at least three differentiation markers, СASP14, IVL (expression increase by 3.9 and 3.7 times respectively in the p53-knockdown cells, p < 0.05) and TGM1 (twofold expression decrease in the p53-knockdown cells, and 1.7-fold expression increase under exposure to Nutlin-3a, p < 0.05) in HaCaT cells is p53-mediated. The positive correlation has been revealed for expression of TGM1 and p53 that might be realized indirectly via ΔNp63 expression alteration. At the same time, modulation of p53 does not result in significant alterations in expression of cytokeratins.

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Analysis of mutation and promoter methylation of TP53 gene in tumors of the head and neck

Current Issues in Pharmacy and Medical Sciences ◽

10.1515/cipms-2016-0011 ◽

2016 ◽

Vol 29 (2) ◽

pp. 53-56

Author(s):

Adrian Jarzynski ◽

Katarzyna Papiernik ◽

Malgorzata Polz-Dacewicz

Keyword(s):

Head And Neck ◽

P53 Protein ◽

Gene Promoter ◽

Tp53 Gene ◽

World Health ◽

Sample Population ◽

Neck Tumors ◽

Health Organization ◽

The Guardian ◽

In Cells

Abstract According to current World Health Organization data, worldwide, cancer is second to cardiovascular diseases as the leading cause of death. The p53 protein is a translation product of the TP53 gene, and it has many functions in cells. Indeed, for this, it is commonly called the “guardian of the genome”. The aim of this study was to evaluate the prevalence of mutation and methylation in the promoter of the TP53 gene in cells affected with squamous cell carcinoma of the head and neck. The research material consisted of 34 DNA samples isolated from surgically removed tissue fragments of head and neck tumors. In this work, analysis of all samples for the presence of mutations proved negative. This result simultaneously revealed an absence of mutation in the TP53 gene promoter in the analyzed material. However, the detection of changes in the methylation profile status of the promoter of the TP53 gene in the DNA samples revealed the presence of both methylated alleles in 76.5% of the sample population, while in the remaining 23.5%, methylation was present in only one allele of the studied gene. In our work, we assumed that samples displaying methylation involving two alleles will show greater predisposition to the development of a malignant tumor. The obtained results reveal that despite the lack of mutation in the TP53 gene promoter, its functioning may be impaired by other mechanisms – either epigenetic or environmental.

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Phenolic Acids from Lycium barbarum Leaves: In Vitro and In Silico Studies of the Inhibitory Activity against Porcine Pancreatic α-Amylase

Processes ◽

10.3390/pr8111388 ◽

2020 ◽

Vol 8 (11) ◽

pp. 1388

Author(s):

Luna Pollini ◽

Alessandra Riccio ◽

Cristina Juan ◽

Carmela Tringaniello ◽

Federica Ianni ◽

...

Keyword(s):

Phenolic Acids ◽

Inhibitory Activity ◽

Leaf Extract ◽

Inhibitory Effect ◽

Dependent Manner ◽

Lycium Barbarum ◽

Plant Materials ◽

Vitro Assay ◽

In Silico Studies

Nowadays, bioactive compounds from vegetable food and waste are of great interest for their inhibitory potential against digestive enzymes. In the present study, the inhibitory activity of methanolic extract from Lycium barbarum leaves on porcine pancreas α-amylase has been studied. The α-amylase inhibitory activity of the constituent phenolic acids was also investigated. The leaves were extracted by ultrasound-assisted method, one of the most efficient techniques for bioactive extraction from plant materials, and then the phenolic acids were identified by Accurate-Mass Quadrupole Time-of-Flight (Q-TOF) Liquid Chromatography/Mass Spectrometry (LC/MS). Chlorogenic and salicylic acids were the most abundant phenolic acids in L. barbarum leaf extract. The inhibitory effect against α-amylase, determined for individual compounds by in vitro assay, was higher for chlorogenic, salicylic, and caffeic acids. L. barbarum leaf extract showed an appreciable α-amylase inhibitory effect in a concentration-dependent manner. Docking studies of the considered phenolic acids into the active site of α-amylase suggested a conserved binding mode that is mainly stabilized through H-bonds and π-π stacking interactions.

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