Review
Biochemistry & Molecular Biology
Maria Luisa Toribio, Sara Gonzalez-Garcia
Summary: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease that arises from the oncogenic transformation of developing T cells during T-lymphopoiesis. Efforts have been made to understand the mechanisms underlying NOTCH1 activation and develop targeted therapies for T-ALL.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Jiachen Wen, Dan Liu, Linxiang Zhao
Summary: Gamma-secretase is a large transmembrane protein complex consisting of four distinct units, which has garnered attention for its role in intramembrane proteolysis. The recent discovery of its atomic structure through cryo-EM has enhanced our understanding of its physiological functions and facilitated the development of novel molecules targeting gamma-secretase. This review focuses on the latest progress of gamma-secretase inhibitors and modulators in clinical and preclinical stages, as well as their potential applications in various biological indications.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Hui Jia, Mingyue Liu, Xinying Wang, Qiyu Jiang, Shu Wang, Ramesh Kumar Santhanam, Chongning Lv, Qingchun Zhao, Jincai Lu
Summary: The study revealed the significant inhibitory effect of Cimigenoside on breast cancer, suppressing proliferation or metastasis of breast cancer cells by targeting the Notch signaling pathway-mediated mitochondrial apoptosis and EMT process.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Yasmin Abedin, Sofia Gabrilovich, Emily Alpert, Erica Rego, Salma Begum, Qingshi Zhao, Debra Heller, Mark H. Einstein, Nataki C. Douglas
Summary: This study found differential expression of Notch signaling pathway in uLMS and suggested that GSIs could be potential therapeutics with limited efficacy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Iowis Zhu, Raymond Liu, Julie M. Garcia, Axel Hyrenius-Wittsten, Dan Piraner, Josef Alavi, Divya Israni, Bin Liu, Ahmad S. Khalil, Kole T. Roybal
Summary: Synthetic biology has the potential to meet clinical requirements by precisely controlling cell function. By systematically engineering key domains involved in regulated intramembrane proteolysis, researchers have developed synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. Engineering human primary T cells with this receptor platform demonstrates its therapeutic potential.
Article
Oncology
Tyler R. McCaw, Evelyn Inga, Herbert Chen, Renata Jaskula-Sztul, Vikas Dudeja, James A. Bibb, Bin Ren, J. Bart Rose
Summary: Gamma secretase inhibitors (GSIs), originally developed as Alzheimer's therapies, have been repurposed as anticancer agents due to their ability to inhibit Notch receptor cleavage. Despite showing promise in preclinical models, GSIs have not demonstrated significant clinical benefit in most solid tumors. Further research is needed to address limitations in understanding GSI mechanisms and improve their efficacy in cancer treatment.
Article
Biology
Michael Collins, Jean-Marie Michot, Christophe Bellanger, Charlotte Mussini, Karim Benhadji, Christophe Massard, Franck Carbonnel
Summary: Inhibition of Notch oncogenic signaling in humans leads to tumor regression and plays a role in intestinal homeostasis. A study in patients with refractory cancer treated with the first-in-human Notch inhibitor LY3039478 revealed abnormal intestinal epithelial cell differentiation and transient diarrhea as side effects, which resolved after discontinuing the drug. The findings confirm the importance of Notch signaling in maintaining intestinal homeostasis in humans.
Article
Immunology
Piyush Baindara, Md Bodruzzaman Sarker, Alexander P. Earhart, Santi M. Mandal, Adam G. Schrum
Summary: This article describes a model in which NOTCH may play a central role in lung infection during COVID-19. A pathway involving NOTCH signaling, furin, ADAM17, and ACE2 may increase viral entry and infection of SARS-CoV-2. NOTCH signaling can also upregulate IL-6 and pro-inflammatory mediators, and if it fails to turn down properly, it may inhibit airway regeneration during lung healing.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Prasoon Agarwal, Aleksandra Glowacka, Loay Mahmoud, Wesam Bazzar, Lars-Gunnar Larsson, Mohammad Alzrigat
Summary: Amplification of the MYCN oncogene in neuroblastoma is associated with high-risk disease and poor prognosis. This study reveals that MYCN-amplified neuroblastoma cells have reduced expression of genes involved in NOTCH receptor processing, axoneme assembly, and membrane protein proteolysis. Genes encoding gamma-secretase complex subunits, known for their role in NOTCH signaling, are down-regulated in MYCN-amplified neuroblastoma. Depletion of MYCN or inhibition of gamma-secretase activity restores the expression of gamma-secretase and NOTCH-target genes. This study provides insight into the molecular mechanisms underlying MYCN's contribution to high-risk neuroblastoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Xin Kang, Zheng-Ping Zhang, Chang-Geng Song, Long Liu, Yan Zhao, Jin-Le Du, Yu-Bo Lai, Xiu-Li Cao, Wen-Min Ye, Yu-Fei Zhang, Min-Hua Zheng, Yu-Hong Zeng, Xiao-Long Sun, Sheng-Xi Wu, Fang Gao
Summary: During neurodevelopment, the differentiation of neural stem/progenitor cells into neurons is regulated by the Notch signaling pathway. In this study, the effect of a Notch signaling blocker, gamma-secretase inhibitor (GSI), on the morphological development of differentiating neurons was investigated. The results showed that GSI application impeded neurite outgrowth and increased the expression of miR-342-5p, a downstream effector of Notch signaling. Furthermore, the shorter neurites induced by GSI could be partially rescued by miR-342-5p inhibitors, indicating the involvement of STAT3 as a possible target of miR-342-5p in this process. These findings provide important insights for future therapeutic research.
NEUROSCIENCE LETTERS
(2022)
Article
Biochemical Research Methods
Jie Li, Jing Li, Haifeng Wang, Jie Qin, Haishan Zeng, Kaige Wang, Shuang Wang
Summary: This study aimed to investigate the dose- and time-dependent effects of the combination of DAPT and cisplatin on osteosarcoma cells using CRMI technology. The results showed significant changes in intracellular composition and subcellular morphology, indicating a synergistic effect between DAPT and cisplatin. Understanding the cellular response at a molecular level provides insights for developing personalized tumor treatment protocols.
BIOMEDICAL OPTICS EXPRESS
(2021)
Article
Biochemistry & Molecular Biology
Atul Kumar Singh, Kumari Sunita Prajapati, Shashank Kumar
Summary: This study demonstrates the potential of hesperidin to bind to the catalytic site of GS and inhibit the Notch signaling pathway, leading to a decrease in cancer stemness and colonosphere formation.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Review
Chemistry, Medicinal
Plaboni Sen, Siddhartha Sankar Ghosh
Summary: The Notch pathway transmits signals through a unique receptor-ligand interaction and functions after receptor cleavage and nuclear localization. The transcriptional regulator of the Notch pathway lies at the intersection of multiple signaling pathways, enhancing cancer aggressiveness. Preclinical and clinical evidence supports the pro-oncogenic function of Notch signaling in various tumor subtypes.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Oncology
Julie A. Means-Powell, Ingrid A. Mayer, Roohi Ismail-Khan, Luis Del Valle, Debra Tonetti, Vandana G. Abramson, Melinda S. Sanders, Richard M. Lush, Claudia Sorrentino, Samarpan Majumder, Lucio Miele
Summary: A phase 1b trial of Notch inhibitor GSI RO4929097 with exemestane in 15 patients with ER+, metastatic breast cancer was conducted. The combination was well-tolerated, with clinical responses observed in a portion of the patients. The results suggest that further investigation should be done on combinations of Notch inhibitors and endocrine therapy in endocrine-refractory breast cancer.
CLINICAL BREAST CANCER
(2022)
Editorial Material
Biochemistry & Molecular Biology
Daniel R. Dries, Gang Yu
Summary: Research showed that gamma-secretase is a potential therapeutic target for Alzheimer's disease, and provided new opportunities for treatment.