Abstract
The dysregulation of Notch signaling is associated with a wide variety of different human cancers. Notch signaling activation mostly relies on the activity of the γ-secretase enzyme that cleaves the Notch receptors and releases the active intracellular domain. It is well-documented that γ-secretase inhibitors (GSIs) block the Notch activity, mainly by inhibiting the oncogenic activity of this pathway. To date, several GSIs have been introduced clinically for the treatment of various diseases, such as Alzheimer’s disease and various cancers, and their impacts on Notch inhibition have been found to be promising. Therefore, GSIs are of great interest for cancer therapy. The objective of this review is to provide a systematic review of in vitro and in vivo studies for investigating the effect of GSIs on various cancer stem cells (CSCs), mainly by modulation of the Notch signaling pathway. Various scholarly electronic databases were searched and relevant studies published in the English language were collected up to February 2020. Herein, we conclude that GSIs can be potential candidates for CSC-targeting therapy. The outcome of our study also indicates that GSIs in combination with anticancer drugs have a greater inhibitory effect on CSCs.
Highlights
Despite the remarkable progress being made in cancer treatment, cancer is the leading cause of death worldwide
The results showed that this treatment increased the anticancer activity and apoptosis, decreased the epithelial to mesenchymal transition, reduced survival signals (EGFR, cyclin E, nuclear factor-κB (NF-κB), and PI3K/Akt pathway; B-cell lymphoma-extra-large (Bcl-xL); and B-cell lymphoma 2 (Bcl-2)), decreased the density of microvessels, and eliminated cancer stem cells (CSCs) in the tumor [149]
Given that Notch signaling is implicated in regulation of the cell fate, the aberrant activation of this pathway can lead to tumorigenesis
Summary
Despite the remarkable progress being made in cancer treatment, cancer is the leading cause of death worldwide. CSCs possess similar stemness properties to normal stem cells, including the differentiation, proliferation, and self-renewal capabilities that create heterogeneous cancer cell populations. There are various functional assays for the isolation of CSCs, such as side population cells, tumorigenicity, immune selection by natural killer cells, the aldehyde dehydrogenases (ALDH) assay, and label-retaining methods [3]. Their tumor-forming capacity is characterized by their increased tumor-repopulating ability when transplanted into immunodeficient mouse models. Sphere formation assays, as in vitro assays, are used for the enrichment and identification of CSCs [5]
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