A balancing act: using small molecules for therapeutic intervention of the p53 pathway in cancer

2020 ◽  
Vol 49 (19) ◽  
pp. 6995-7014 ◽  
Author(s):  
Jessica J. Miller ◽  
Christian Gaiddon ◽  
Tim Storr
Keyword(s):  
Small Molecules ◽  
Therapeutic Intervention ◽  
P53 Protein ◽  
P53 Pathway ◽  
Cancer Types

Small molecules targeting various aspects of the p53 protein pathway have shown significant promise in the treatment of a number of cancer types.

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

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3737
Author(s):  
Joana Moreira ◽  
Joana Almeida ◽  
Lucília Saraiva ◽  
Honorina Cidade ◽  
Madalena Pinto
Keyword(s):  
Antitumor Agents ◽  
P53 Protein ◽  
Cancer Therapeutics ◽  
Tp53 Gene ◽  
Inhibitory Effect ◽  
Pharmacokinetic Parameters ◽  
P53 Pathway ◽  
Protein Inhibition ◽  
In Silico Studies ◽  
Binding Cleft

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.

scholarly journals Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3476
Author(s):  
Surinder M. Soond ◽  
Lyudmila V. Savvateeva ◽  
Vladimir A. Makarov ◽  
Neonila V. Gorokhovets ◽  
Paul A. Townsend ◽  
...  
Keyword(s):  
Cell Death ◽  
P53 Protein ◽  
Genetic Locus ◽  
Signal Transduction Pathway ◽  
Tumor Suppressor P53 ◽  
Regulatory Relationship ◽  
Cathepsin Proteases ◽  
Recent Developments ◽  
Cancer Types ◽  
The Guardian

While viewed as the “guardian of the genome”, the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies.

scholarly journals Strategies for manipulating the p53 pathway in the treatment of human cancer

2000 ◽  
Vol 352 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Ted R. HUPP ◽  
David P. LANE ◽  
Kathryn L. BALL
Keyword(s):  
Cancer Progression ◽  
Human Cancer ◽  
P53 Protein ◽  
Metastatic Potential ◽  
Biochemical Properties ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
P53 Pathway ◽  
Environmental Pressures ◽  
Human Cancers

Human cancer progression is driven in part by the mutation of oncogenes and tumour-suppressor genes which, under selective environmental pressures, give rise to evolving populations of biochemically altered cells with enhanced tumorigenic and metastatic potential. Given that human cancers are biologically and pathologically quite distinct, it has been quite surprising that a common event, perturbation of the p53 pathway, occurs in most if not all types of human cancers. The central role of p53 as a tumour-suppressor protein has fuelled interest in defining its mechanism of function and regulation, determining how its inactivation facilitates cancer progression, and exploring the possibility of restoring p53 function for therapeutic benefit. This review will highlight the key biochemical properties of p53 protein that affect its tumour-suppressor function and the experimental strategies that have been developed for the re-activation of the p53 pathway in cancers.

scholarly journals Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 272 ◽  
Author(s):  
Silvia Pietrobono ◽  
Barbara Stecca
Keyword(s):  
Small Molecules ◽  
Anticancer Therapy ◽  
Clinical Settings ◽  
Clinical Use ◽  
Mechanisms Of Resistance ◽  
Tumor Initiating Cells ◽  
Promising Therapeutic Target ◽  
Gli Transcription Factors ◽  
Cancer Types ◽  
Hh Signaling

Hedgehog-GLI (HH) signaling was originally identified as a critical morphogenetic pathway in embryonic development. Since its discovery, a multitude of studies have reported that HH signaling also plays key roles in a variety of cancer types and in maintaining tumor-initiating cells. Smoothened (SMO) is the main transducer of HH signaling, and in the last few years, it has emerged as a promising therapeutic target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been hampered by severe side effects, low selectivity against cancer stem cells, and the onset of mutation-driven drug resistance. Moreover, SMO antagonists are not effective in cancers where HH activation is due to mutations of pathway components downstream of SMO, or in the case of noncanonical, SMO-independent activation of the GLI transcription factors, the final mediators of HH signaling. Here, we review the current and rapidly expanding field of SMO small-molecule inhibitors in experimental and clinical settings, focusing on a class of acylguanidine derivatives. We also discuss various aspects of SMO, including mechanisms of resistance to SMO antagonists.

MicroRNA (miR)-29 Modified Bone Marrow Stem Cells (BMSCs) Regulating Wnt-β-Catenin-p53 Pathway to Inhibit the Migration and Proliferation of Conjunctival Fibroblasts

2021 ◽  
Vol 11 (8) ◽  
pp. 1517-1523
Author(s):  
Shibo Xiong ◽  
Pengcheng Huang ◽  
Sumin Xu ◽  
Aimin Li
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
P53 Protein ◽  
Fibroblast Cell ◽  
Scratch Test ◽  
Bone Marrow Stem Cells ◽  
Control Group ◽  
P53 Pathway ◽  
Protein Expressions ◽  
And Migration

To explore the mechanism of miR-29 modified bone marrow stem cells (BMSCs) in regulating the Wnt/β-Catenin-p53 pathway to inhibit the migration and proliferation of conjunctival fibroblasts. New Zealand rabbit BMSCs were randomly divided into control group, miR-29NC group, and miR-29mimic group. MTT assay, cell scratch test, and Western blot were used to detect the proliferation, migration, and protein expressions in constituent fibroblast. Cell proliferation in the miR-29mimic group was attenuated at 24 h and 48 h (P <0.05). The expression of miR-29 in miR-29 mimic group was upregulated, while Wnt/β-Catenin-p53 protein was decreased (P < 0.05). MiR-29 modified BMSC can inhibit the expression of Wnt/β-Catenin-p53 pathway and suppress the proliferation and migration of conjunctival fibroblasts.

scholarly journals SCYL1BP1 modulates neurite outgrowth and regeneration by regulating the Mdm2/p53 pathway

2012 ◽  
Vol 23 (23) ◽  
pp. 4506-4514 ◽  
Author(s):  
Yonghua Liu ◽  
Ying Chen ◽  
Xiang Lu ◽  
Youhua Wang ◽  
Yinong Duan ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Cortical Neurons ◽  
Axonal Regeneration ◽  
P53 Protein ◽  
Transcriptional Activator ◽  
Small Interfering Rnas ◽  
P53 Pathway ◽  
Neuronal Morphogenesis

SCY1-like 1–binding protein 1 (SCYL1BP1) is a newly identified transcriptional activator domain containing a protein with many unknown biological functions. Recently emerging evidence has revealed that it is a novel regulator of the p53 pathway, which is required for neurite outgrowth and regeneration. Here we present evidence that SCYL1BP1 inhibits nerve growth factor–mediated neurite outgrowth in PC12 cells and affects morphogenesis of primary cortical neurons by strongly decreasing the p53 protein level in vitro, all of which depends on SCYL1BP1's transcriptional activator domain. Exogenous p53 rescues neurite outgrowth and neuronal morphogenesis defects caused by SCYL1BP1. Furthermore, SCYL1BP1 can directly induce Mdm2 transcription, whereas inhibiting the function of Mdm2 by specific small interfering RNAs results in partial rescue of neurite outgrowth and neuronal morphogenesis defects induced by SCYL1BP1. In vivo experiments show that SCYL1BP1 can also depress axonal regeneration, whereas inhibiting the function of SCYL1BP1 by specific short hairpin RNA enhances it. Taken together, these data strongly suggested that SCYL1BP1 is a novel transcriptional activator in neurite outgrowth by directly modulating the Mdm2/p53-dependent pathway, which might play an important role in CNS development and axonal regeneration after injury.

scholarly journals Structure vs. Function of TRIB1—Myeloid Neoplasms and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3060
Author(s):  
Hamish D McMillan ◽  
Karen Keeshan ◽  
Anita K Dunbier ◽  
Peter D Mace
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Tumour Progression ◽  
Conformational Switching ◽  
Myeloid Neoplasms ◽  
Exciting Potential ◽  
Cancer Types ◽  
Prostate Cancers ◽  
Predict Treatment Response

The Tribbles family of proteins—comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40—play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most well-understood role of TRIB1 is in acute myeloid leukaemia, where it can regulate C/EBP transcription factors and kinase pathways. Structure–function studies have uncovered conformational switching of TRIB1 from an inactive to an active state when it binds to C/EBPα. This conformational switching is centred on the active site of TRIB1, which appears to be accessible to small-molecule inhibitors in spite of its inability to bind ATP. Beyond myeloid neoplasms, TRIB1 plays diverse roles in signalling pathways with well-established roles in tumour progression. Thus, TRIB1 can affect both development and chemoresistance in leukaemia; glioma; and breast, lung and prostate cancers. The pervasive roles of TRIB1 and other Tribbles proteins across breast, prostate, lung and other cancer types, combined with small-molecule susceptibility shown by mechanistic studies, suggests an exciting potential for Tribbles as direct targets of small molecules or biomarkers to predict treatment response.

Polyclonal antibody to porcine p53 protein: A new tool for studying the p53 pathway in a porcine model

2008 ◽  
Vol 377 (1) ◽  
pp. 151-155 ◽  
Author(s):  
Yafeng Qiu ◽  
Yang Shen ◽  
Xiangdong Li ◽  
Qingwei Liu ◽  
Zhiyong Ma
Keyword(s):  
Polyclonal Antibody ◽  
Porcine Model ◽  
P53 Protein ◽  
Protein A ◽  
P53 Pathway

Oxidative stress is involved in the UV activation of p53

1996 ◽  
Vol 109 (5) ◽  
pp. 1105-1112
Author(s):  
J. Renzing ◽  
S. Hansen ◽  
D.P. Lane
Keyword(s):  
Oxidative Stress ◽  
Ionizing Radiation ◽  
Ultraviolet Light ◽  
P53 Protein ◽  
Biological Response ◽  
Dna Lesions ◽  
P53 Pathway ◽  
Tumour Suppressor Protein ◽  
P53 Response ◽  
Photochemical Modification

In many vertebrate cells exposure to ultraviolet light lead to a dramatic increase in the cellular levels of the tumour suppressor protein p53, followed by a biological response of either growth arrest or programmed cell death. Ultraviolet light can be absorbed directly by cellular macromolecules, leading to photochemical modification of DNA and proteins. Additionally, it also causes free radical formation, resulting in oxidative stress. Whereas ultraviolet light and ionizing radiation both induce DNA lesions which trigger an activation of the p53 pathway, the magnitude of the p53 response elicited by ionizing radiation is comparatively low. Following irradiation with ultraviolet light two populations of p53-reactive cells are induced: a population accumulating high levels of p53 protein and a population with comparatively low levels of p53, similar in magnitude to the p53 response following ionizing radiation. Pretreatment of cells with N-acetylcysteine, an agent known to counteract oxidative stress, attenuates the cellular p53 response to ultraviolet light by reducing the number of cells with high p53 levels but does not affect the response to ionizing radiation. We demonstrate that N-acetylcysteine pretreatment does not prevent the inflicted DNA damage and therefore conclude that oxidative stress is a causative agent in the ultraviolet light activation of the p53 pathway.

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