Article
Biochemistry & Molecular Biology
Kester Mo Henningsen, Valentina Manzini, Anna Magerhans, Sabrina Gerber, Matthias Dobbelstein
Summary: MDM2 can remove p53 from promoters by rapidly terminating its interactions with chromatin in a ubiquitin-dependent manner, in addition to its antagonism through covering the transactivation domain and destabilization.
Review
Biochemistry & Molecular Biology
Lucia Haronikova, Ondrej Bonczek, Pavlina Zatloukalova, Filip Kokas-Zavadil, Martina Kucerikova, Philip J. Coates, Robin Fahraeus, Borivoj Vojtesek
Summary: This review discusses the mechanism of action, determinants of sensitivity, and resistance issues of MDM2 inhibitors, emphasizing the need for patient stratification based on these aspects to achieve better clinical responses.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2021)
Review
Biochemistry & Molecular Biology
Neha Bhatia, Rakesh Khator, Swanand Kulkarni, Yogesh Singh, Pradeep Kumar, Suresh Thareja
Summary: The discovery of MDM2 and MDM2-p53 interaction inhibitors has revolutionized anticancer research due to their involvement in about 50% of cancer cases globally. In addition to inhibiting MDM2, targeting the interaction between MDM2 and p53 has proven to be an effective strategy for anticancer drug development. Both natural and synthetic molecules have shown promising MDM2 inhibitory potential. This review focuses on the pathophysiology of the MDM2-p53 interaction loop, characteristics of the active site, and the efficacy of various inhibitors from recent patents.
CURRENT MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Rui Shi, Zirong Liu
Summary: RPL15 plays crucial roles in the progression and metastasis of hepatocellular carcinoma (HCC), serving as a promising candidate for targeted therapies.
CANCER CELL INTERNATIONAL
(2022)
Review
Oncology
Arianna Romani, Enrico Zauli, Giorgio Zauli, Saleh AlMesfer, Samar Al-Swailem, Rebecca Voltan
Summary: MDM2 is the main inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The short half-life of p53 in normal cells and tissues may have potential harmful effects if its levels increase uncontrollably. While p53 mutations are rare in retinoblastoma, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. This minireview discusses the potential use of nutlin-3, a prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for treating retinoblastoma. The review also explores the relative contribution of p53-mediated gene transcription and mitochondrial perturbation to retinoblastoma treatment.
FRONTIERS IN ONCOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Wen-fang Li, Leader Alfason, Can Huang, Yu Tang, Li Qiu, Makoto Miyagishi, Shou-rong Wu, Vivi Kasim
Summary: This study reveals that p52-ZER6 may be a potential biomarker for determining patients appropriate for MDM2-p53 binding inhibition-based antitumor therapy, and demonstrates the potential of combinatorial therapy using MDM2-p53 binding inhibitors and p52-ZER6 inhibition.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Oncology
Konstantina Psatha, Laxmikanth Kollipara, Elias Drakos, Elena Deligianni, Konstantinos Brintakis, Eustratios Patsouris, Albert Sickmann, George Z. Rassidakis, Michalis Aivaliotis
Summary: The activation of wild-type p53 protein in human lymphoma is a promising therapeutic strategy. An in vitro integrative comparative multi-omics analysis of different lymphoma types before and after p53 activation can shed light on the molecular mechanisms involved. Our findings provide valuable insights into the role of specific proteins and pathways in lymphoma pathogenesis and the global effect of nutlin-3a, which can guide targeted studies on lymphoma progression and resistance.
Article
Biochemistry & Molecular Biology
Tatyana Grigoreva, Aleksandra Sagaidak, Angelina Romanova, Daria Novikova, Aleksander Garabadzhiu, Viacheslav Tribulovich
Summary: The development of chemoresistance in colorectal cancer cells was replicated in vitro by gradually increasing the drug content in the medium, resulting in reduced sensitivity to drugs of different mechanisms of action in resistant cell lines. The cells were found to utilize a universal efflux defense mechanism, which could be partially neutralized by inhibitors of ABC transport proteins, such as P-glycoprotein, confirming its role in chemoresistance.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Article
Biochemistry & Molecular Biology
Sergio Garrido-Jimenez, Juan Francisco Barrera-Lopez, Selene Diaz-Chamorro, Clara Maria Mateos-Quiros, Ignacio Rodriguez-Blanco, Francisca Lourdes Marquez-Perez, Maria Jesus Lorenzo, Francisco Centeno, Angel Carlos Roman, Jose Maria Carvajal-Gonzalez
Summary: Proper physiological function of mammalian airways relies on the differentiation and self-renewal ability of basal stem cells, with p53 playing a crucial role in regulating this process. The MDM2-p53 signaling pathway is important for maintaining basal stem cell differentiation and proper cell proliferation in the airway epithelium, suggesting it as a potential target for controlling epithelial regeneration.
Article
Pharmacology & Pharmacy
Giada Lodi, Valentina Gentili, Fabio Casciano, Arianna Romani, Giorgio Zauli, Paola Secchiero, Enrico Zauli, Carolina Simioni, Silvia Beltrami, Mercedes Fernandez, Roberta Rizzo, Rebecca Voltan
Summary: SARS-CoV viruses downregulate antiviral defenses by manipulating p53, a key molecule for cell homeostasis and immune control. Using MDM2 inhibitors to raise p53 levels can inhibit cell cycle and virus release, as well as reduce the expression of inflammatory cytokines. Therefore, p53 and MDM2 inhibitors may be potential therapies against SARS-CoV-2.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Medicine, General & Internal
Giorgio Zauli, Sara AlHilali, Samar Al-Swailem, Paola Secchiero, Rebecca Voltan
Summary: This review summarizes the ocular manifestations and transmission of SARS-CoV-2 infection, and suggests the potential use of small molecule non-genotoxic inhibitors to protect the eyes from infection.
FRONTIERS IN MEDICINE
(2022)
Article
Oncology
Irene Veneziani, Paola Infante, Elisa Ferretti, Ombretta Melaiu, Cecilia Battistelli, Valeria Lucarini, Mirco Compagnone, Carmine Nicoletti, Aurora Castellano, Stefania Petrini, Marzia Ognibene, Annalisa Pezzolo, Lucia Di Marcotullio, Roberto Bei, Lorenzo Moretta, Vito Pistoia, Doriana Fruci, Vincenzo Barnaba, Franco Locatelli, Loredana Cifaldi
Summary: The study demonstrated that Nutlin-3a could enhance NK cell-mediated killing of neuroblastoma cells by restoring p53 function and increasing ligand expression for NK-ARs. Adoptive transfer of human NK cells into neuroblastoma-bearing mice resulted in tumor shrinkage and improved overall survival. Nutlin-3a also boosted NK cell-mediated cytotoxicity against neuroblastoma spheroids by increasing ligand expression in primary neuroblastoma cells.
CANCER IMMUNOLOGY RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Yali Wang, Bo Ji, Zhongshui Cheng, Lianghui Zhang, Yingying Cheng, Yingying Li, Jin Ren, Wenbo Liu, Yuanyuan Ma
Summary: A series of novel indolone derivatives were synthesized and evaluated for their binding affinities toward MDM2 and MDMX. Compound A13 showed the most potent affinity and exhibited strong inhibitory effects on multiple cancer cell lines.
Review
Chemistry, Medicinal
Chahat, Rohit Bhatia, Bhupinder Kumar
Summary: Cancer is a dangerous disease and p53 is a well-researched tumor suppressor protein that plays a critical role in maintaining genetic stability and controlling various cellular processes. Abnormalities in p53 contribute to genetic instability and carcinogenesis. Enhancing p53 activity in cancer cells is a promising anticancer strategy. This article discusses the current advancements in anti-tumor activities targeting p53-MDM2 and emphasizes the structure-activity relationship characteristics (SAR).
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Jihyun Lee, Jongdoo Kim, Eun Mi Kim, Ukjin Kim, A-Ram Kang, Jong Kuk Park, Hong-Duck Um
Summary: In this study, it was found that p21 acts as a negative regulator of p53 stability, reducing the cellular levels of p53 protein and promoting its degradation. Additionally, p21 promotes the interaction between p53 and Wip1, and forms a trimeric complex with Wip1. The p21/p53 complex is more efficient in facilitating the binding of p53 to Wip1 and Mdm2, suggesting that p21 may be a potential target to restore p53 activity in cancer cells.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Cell Biology
Veronica Gatti, Manuela Ferrara, Ilaria Virdia, Silvia Matteoni, Laura Monteonofrio, Simona di Martino, Maria Grazia Diodoro, Giuliana Di Rocco, Cinzia Rinaldo, Silvia Soddu
Article
Cell Biology
Francesca Sardina, Laura Monteonofrio, Manuela Ferrara, Fiorenza Magi, Silvia Soddu, Cinzia Rinaldo
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2020)
Article
Biology
Francesca Sardina, Alessandra Pisciottani, Manuela Ferrara, Davide Valente, Marialuisa Casella, Marco Crescenzi, Angelo Peschiaroli, Carlo Casali, Silvia Soddu, Andrew J. Grierson, Cinzia Rinaldo
LIFE SCIENCE ALLIANCE
(2020)
Article
Oncology
Alessandra Verdina, Micol Di Segni, Carla Amoreo, Isabella Sperduti, Simonetta Buglioni, Marcella Mottolese, Giuliana Di Rocco, Silvia Soddu
Summary: The study suggests that HIPK2 may serve as a potential predictive marker for adjuvant-treated stage II CRC and for prospective therapy with NRF2 modulators, as high percentage of HIPK2(+) cells was associated with therapeutic vulnerability in stage II CRC. Additionally, HIPK2 depletion induced resistance to 5-FU and OXA, while sensitivity to these drugs was further induced by brusatol supplementation in HIPK2-proficient cells.
Article
Multidisciplinary Sciences
Elena Paccosi, Federico Costanzo, Michele Costantino, Alessio Balzerano, Laura Monteonofrio, Silvia Soddu, Giorgio Prantera, Stefano Brancorsini, Jean-Marc Egly, Luca Proietti-De-Santis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Cell Biology
Rossella Luca, Maria Rita Assenza, Fabio Maiullari, Luisa Pieroni, Silvia Maiullari, Giulia Federici, Federica Marini, Roberto Rizzi, Andrea Urbani, Silvia Soddu, Fabiola Moretti
Summary: MDM4 impairs the metastatic process of EOC by inhibiting mTOR activity, reducing cell migration. High levels of MDM4 expression are associated with significantly increased 15-year survival rate and negative impact on the efficacy of mTOR inhibitors.
CELL DEATH & DISEASE
(2021)
Article
Oncology
Xiaolei Zhou, Madhurendra Singh, Gema Sanz Santos, Vincent Guerlavais, Luis A. Carvajal, Manuel Aivado, Yue Zhan, Mariana M. S. Oliveira, Lisa S. Westerberg, D. Allen Annis, John Inge Johnsen, Galina Selivanova
Summary: Activation of p53 by MDM2 inhibitors induces the expression of ERVs, partly through epigenetic factors LSD1 and DNMT1. The IFN response caused by ERV derepression upon p53-targeting therapies provides a potential way to overcome immune checkpoint blockade resistance and transform cold tumors into hot.
Article
Biology
Benedetta M. Santoliquido, Michela Frenquelli, Claudia Contadini, Stefano Bestetti, Marco Gaviraghi, Elisa Barbieri, Anna De Antoni, Luca Albarello, Angelo Amabile, Alessandro Gardini, Angelo Lombardo, Claudio Doglioni, Paolo Provero, Silvia Soddu, Davide Cittaro, Giovanni Tonon
Summary: The study revealed that genes within common fragile sites (CFS) may be down-regulated or overexpressed, affecting tumor immune recognition. Particularly, in some CFS, genes are unexpectedly overexpressed, potentially leading to aberrant mitosis in cells. Furthermore, some CFS are associated with mitotic gene deregulation and genomic instability.
LIFE SCIENCE ALLIANCE
(2021)
Article
Biochemistry & Molecular Biology
Marie-Stephanie Aschtgen, Konstantinos Fragkoulis, Gema Sanz, Staffan Normark, Galina Selivanova, Birgitta Henriques-Normark, Sylvain Peuget
Summary: There is increasing evidence suggesting the involvement of bacteria in the development of cancer, although the underlying molecular mechanisms are not well understood. In this study, the researchers found that lipopolysaccharides from bacteria such as Klebsiella pneumoniae inhibit the tumor suppressor p53 pathway through a novel mechanism. They discovered that the lipopolysaccharides destabilize TP53 mRNA through the TLR4-NF-kappa B-mediated inhibition of the RNA-binding factor Wig-1. Moreover, they found a correlation between the levels of TLR4 and p53 mutation in colorectal tumors, suggesting that the repression of p53 by bacteria may shape the genomic evolution of cancer.
Article
Genetics & Heredity
Sara Biagiotti, Ambra Barone, Mattia Paolo Aliano, Giulia Federici, Marco Malatesta, Caterina Caputi, Silvia Soddu, Vincenzo Leuzzi, Luciana Chessa, Mauro Magnani
Summary: Most ATM variants associated with Ataxia Telangiectasia are classified as variants with uncertain significance. This study focused on a specific ATM variant found in Lebanese brothers, revealing it to be pathogenic even though it causes an atypical phenotype. Dexamethasone showed therapeutic potential on this and possibly other missense ATM variants.
FRONTIERS IN GENETICS
(2021)
Editorial Material
Oncology
Sylvain Peuget, Galina Selivanova
Summary: p53 is a complex cell signaling hub that controls the expression of multiple target genes in response to different stimuli, with the exact code by which p53 integrates these stresses into transcriptional responses still unclear. Regulation of p53 at various levels leads to a wide diversity in p53 complexes on target promoters, providing adaptability to its transcriptional program. Understanding the mechanisms by which p53 selectively directs desired outcomes in cancer cells is crucial as p53-targeted therapies progress, with further investigations needed on cell type- and stimuli-dependent transcriptional outcomes by p53.
Article
Biochemistry & Molecular Biology
Vera V. Grinkevich, Aparna Vema, Karin Fawkner, Natalia Issaeva, Virginia Andreotti, Eleanor R. Dickinson, Elisabeth Hedstrom, Clemens Spinnler, Alberto Inga, Lars-Gunnar Larsson, Anders Karlen, Margareta Wilhelm, Perdita E. Barran, Andrei L. Okorokov, Galina Selivanova, Joanna E. Zawacka-Pankau
Summary: This study reports a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus, which promotes inhibition of both p53/MDM2 and p53/MDM4 interactions. The results may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Oncology
Yue Zhan, Xiaolei Zhou, Sylvain Peuget, Madhurendra Singh, Brian D. Peyser, Zhimin Fan, Galina Selivanova
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Oncology
Xiaolei Zhou, Gema Sanz Santos, Yue Zhan, Mariana M. S. Oliveira, Shiva Rezaei, Madhurendra Singh, Sylvain Peuget, Lisa S. Westerberg, John Inge Johnsen, Galina Selivanova
Summary: This study reveals that breast carcinomas with mtp53 display enhanced inflammation, and that APR-246 can enhance interferon response or repress immune checkpoints to restore cancer immune surveillance.
BRITISH JOURNAL OF CANCER
(2022)
Editorial Material
Oncology
Sylvain Peuget, Galina Selivanova
Summary: In this issue of Cancer Discovery, Adams and colleagues report the discovery of a powerful PROTAC, MDM2 degrader, which activates wild-type p53 and induces cancer cell death. They demonstrate through in vitro and in vivo experiments that the depletion of MDM2 by PROTAC effectively kills p53-mutant or p53-null cancer cells.