Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy

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.

NOTCH localizes to mitochondria through the TBC1D15-FIS1 interaction and is stabilized via blockade of E3 ligase and CDK8 recruitment to reprogram tumor-initiating cells

“…Consequently the development of therapeutics based on NOTCH signaling remains an elusive goal. Deregulation of the NOTCH signaling pathway plays a crucial role in the maintenance and survival of cancer stem cells (CSCs), which likely underlies the observed resistance to chemotherapy 19 , 20 .…”

Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies

“…XNW7201 has been considered a potential new drug for advanced solid tumors due to the ability to block Wnt protein activity, and corresponding clinical trials have been conducted (NCT03901950). The inhibitors of the Notch signaling pathway in CSC research mainly target γ secretory enzymes or Notch ligands [126,129]. The use of Notch inhibitor DAPT (γ secretory enzymes inhibitor) has been shown to reduce the number of renal CSCs and repress growth [128].…”

Modulation of Notch Signaling by Small-Molecular Compounds and Its Potential in Anticancer Studies

“…Like IMR-1 and IMR-1A, SAHM1 attenuates Notch signaling by blocking the MAML/RPB-J interaction and its antitumor effects have been reported against bladder cancer [192] and acute myeloid leukemia [193]. However, SAHM1 showed no significant effects on B-cell acute lymphoblastic leukemia (B-ALL) In addition to DAPT, there are several extensively studied and tested GSI used to prevent NOTCH activation in cancer, including benzazepines such as Dibenzazepine (DBZ; YO-01027) [148][149][150], Crenigacestat (LY3039478) [151,152], LY411575 [153], and RO4929097 [154,155], sulfonamide derivatives such as Avagacestat (BMS-708163) [156,157], MK-0752 [158] and Venetoclax [159], or even natural compounds such as Hesperidin, a polyphenolic glycoside flavonoid that has shown anticancer potential in a colon cancer model [160]. In a broader sense, this further includes additional natural compounds such as Curcumin [161] or Evodiamine, an indole alkaloid that inhibits NOTCH3 signaling in a lung cancer model [162].…”