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Notch1 in cancer therapy: possible clinical implications and challenges

Item Type:Review
Title:Notch1 in cancer therapy: possible clinical implications and challenges
Creators Name:Gharaibeh, L. and Elmadany, N. and Alwosaibai, K. and Alshaer, W.
Abstract:The Notch family consists of four highly conserved transmembrane receptors, the release of the active intracellular domain requires the enzymatic activity of gamma secretase. Notch is involved in embryonic development and in many physiological processes of normal cells where it regulates growth, apoptosis and differentiation. Notch 1, a member of the Notch family, is implicated in many types of cancer, including breast cancer (especially triple negative breast cancer), leukemias, brain tumors, and many others. Notch 1 is tightly connected to many signaling pathways that are therapeutically involved in tumorigenesis. Together, they impact apoptosis, proliferation, chemosensitivity, immune-response and the population of cancer stem cells. Notch 1 inhibition can be achieved through various and diverse methods, among the most common are the gamma secretase inhibitors which produce a pan-Notch inhibition, or the use of Notch 1 siRNA or Notch 1 monoclonal antibodies (mAb) which produce a more specific blockade. Downregulation of Notch 1 can be used alone or in combination with chemotherapy where a synergistic effect and a decrease in chemoresistance can be achieved. Targeting Notch1 in cancers that harbor high expression levels of Notch 1 offers an addition to therapeutic strategies recruited for managing cancer. Considering available evidence, Notch 1 offers a legitimate target that might be incorporated in future strategies for combating cancer. In this review, the possible clinical applications of Notch 1 inhibition and the obstacles that hinder its clinical application are discussed. SIGNIFICANCE STATEMENT: Notch 1 plays an important role in different types of cancer. Numerous approaches of Notch 1 inhibition possess potential benefits in the management of various clinical aspects of cancer. The application of different Notch 1 inhibition modalities faces many challenges.
Keywords:Monoclonal Antibodies, Neoplasms, Notch1 Receptor, Signal Transduction, Animals
Source:Molecular Pharmacology
Publisher:American Society for Pharmacology and Experimental Therapeutics
Page Range:559-576
Date:1 November 2020
Official Publication:https://doi.org/10.1124/molpharm.120.000006
PubMed:View item in PubMed

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