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)
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
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
Biochemistry & Molecular Biology
Atul Kumar Singh, Mohd Shuaib, Kumari Sunita Prajapati, Shashank Kumar
Summary: The study reveals that rutin can inhibit the notch signaling pathway and reduce the stemness/self-renewal property in colon cancer cells and colonospheres by targeting gamma secretase.
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
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)
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)
Review
Medicine, Research & Experimental
Hui Jia, Zuojun Wang, Jingyi Zhang, Fan Feng
Summary: The gamma-secretase complex plays a crucial role in the activation and regulation of the Notch pathway, which is closely associated with the occurrence and development of various types of tumors. This review provides a detailed description of the basic situation and biological functions of the gamma-secretase complex, as well as its applications in the treatment of breast cancer and liver cancer.
Article
Dermatology
Siri Hansen Stabell, Anastasia Renzi, Hogne Roed Nilsen, Olaf Harald Antonsen, Johanna Hol Fosse, Guttorm Haraldsen, Olav Sundnes
Summary: Notch signalling plays a crucial role in multiple human diseases, but the activation status of Notch signalling in patients with familial hidradenitis suppurativa (HS) has not been thoroughly studied. This study established immunostaining protocols to identify activated Notch receptors in human skin tissue and confirmed the ability to detect changes in Notch activation using an ex vivo skin organ model. The results showed the distribution of active Notch signalling in human apocrine-bearing skin and demonstrated a reduced activation of Notch in the epidermis of lesional HS.
EXPERIMENTAL DERMATOLOGY
(2023)
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)
Review
Biochemistry & Molecular Biology
Chuanxi Zheng, Jianghong Huang, Gang Xu, Wei Li, Xin Weng, Shiquan Zhang
Summary: Desmoid tumor (DT) is a rare fibroblastic soft-tissue neoplasm that is characterized by local aggressiveness but no metastatic potential. Aberrant activation of Wnt/beta-catenin signaling and Notch pathway is closely associated with the development and progression of DT, suggesting potential therapeutic targets. Two gamma-secretase inhibitors are currently under extensive investigation and have shown potential treatment benefits in clinical trials.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2024)
Review
Biochemistry & Molecular Biology
Maryam Ghanbari-Movahed, Zahra Ghanbari-Movahed, Saeideh Momtaz, Kaitlyn L. Kilpatrick, Mohammad Hosein Farzaei, Anupam Bishayee
Summary: The dysregulation of Notch signaling is associated with various human cancers, and GSIs have shown promising potential in inhibiting cancer cell growth by blocking this pathway. GSIs may be potential candidates for CSC-targeted therapy, especially when used in combination with anticancer drugs to enhance the inhibitory effect on CSCs.
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
Anja C. Nagel, Dominik Mueller, Mirjam Zimmermann, Anette Preiss
Summary: The membrane-bound Notch regulator (Mnr) supports Notch signaling by promoting the cleavage of the Notch receptor, which in turn enhances Notch receptor activation. Overexpression of Mnr stimulates γ-secretase activity, while knockdown of Mnr inhibits this activity, demonstrating Mnr as a positive regulator of Notch signaling.
Review
Oncology
Chakresh Kumar Jain, Shreya Bhargava, Isha Jain, Srishti Varshney
Summary: The Notch signaling pathway is crucial for cell fate and proliferation, playing a significant role in oncogenesis. Researchers can utilize genetic defects within this pathway to develop promising diagnostic and therapeutic tools for cancer. Inhibiting the Notch pathway offers a new avenue for cancer research and treatment.
RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY
(2022)