A novel triazole, NMK-T-057, induces autophagic cell death in breast cancer cells by inhibiting ?-secretase-mediated activation of Notch signaling.

ABSTRACT: Notch signaling is reported to be deregulated in several malignancies, including breast, and the enzyme ?-secretase plays an important role in the activation and nuclear translocation of Notch intracellular domain (NICD). Hence, pharmacological inhibition of ?-secretase might lead to the subsequent inhibition of Notch signaling in cancer cells. In search of novel ?-secretase inhibitors (GSIs), we screened a series of triazole-based compounds for their potential to bind ?-secretase and observed that 3-(3'4',5'-trimethoxyphenyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole compound (also known as NMK-T-057) can bind to ?-secretase complex. Very interestingly, NMK-T-057 was found to inhibit proliferation, colony-forming ability, and motility in various breast cancer (BC) cells such as MDA-MB-231, MDA-MB-468, 4T1 (triple-negative cells), and MCF-7 (estrogen receptor (ER)/progesterone receptor (PR)-positive cell line) with negligible cytotoxicity against noncancerous cells (MCF-10A and peripheral blood mononuclear cells). Furthermore, significant induction of apoptosis and inhibition of epithelial-to-mesenchymal transition (EMT) and stemness were also observed in NMK-T-057-treated BC cells. The in silico study revealing the affinity of NMK-T-057 toward ?-secretase was further validated by a fluorescence-based ?-secretase activity assay, which confirmed inhibition of ?-secretase activity in NMK-T-057-treated BC cells. Interestingly, it was observed that NMK-T-057 induced significant autophagic responses in BC cells, which led to apoptosis. Moreover, NMK-T-057 was found to inhibit tumor progression in a 4T1-BALB/c mouse model. Hence, it may be concluded that NMK-T-057 could be a potential drug candidate against BC that can trigger autophagy-mediated cell death by inhibiting ?-secretase-mediated activation of Notch signaling.

SUBMITTER: Das A 

PROVIDER: S-EPMC6497959 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature