A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth

Frontiers in Pharmacology

Pharmacology

Amandeep Singh¹  Arun K. Sharma¹  Chendil Damodaran²  Vaibhav Shukla²  Ashish Tyagi²  Uttara Saran²  Balaji Chandrasekaran² 

[1] Penn State Cancer Institute, College of Medicine, The Pennsylvania State University, Hershey, PA, United States;Texas A&M University, College Station, TX, United States;

关键词: breast cancer;    breast cancer stem cell (BCSC);    ASR490;    autophagy;    NOTCH1;   

DOI  :  10.3389/fphar.2023.1150774

 received in 2023-01-24, accepted in 2023-02-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

Although breast cancer stem cells (BCSCs) are well characterized, molecularly targeting and eradicating this sub-population remains a challenge in the clinic. Recent studies have explored several signaling pathways that govern stem cell activation: We and others established that the Notch1 signaling plays a significant role in the proliferation, survival, and differentiation of BCSCs. Earlier, we reported that a newly developed small molecule, ASR490, binds to the negative regulatory region (NRR: The activation switch of the Notch receptor) of Notch1. In vitro results demonstrated that ASR490 significantly inhibited BCSCs (ALDH+ and CD44+/CD24–) and breast cancer (BC) growth at nM concentrations, and subsequently inhibited the colony- and mammosphere-forming abilities of BCSCs and BCs. ASR490 downregulated the expressions of Notch1 intracellular domain (NICD: The active form of Notch1) and its downstream effectors Hey1 and HES1. Inhibition of Notch1-NICD facilitated autophagy-mediated growth inhibition by triggering the fusion of autophagosome and autolysosome in BCSCs. ASR490 was found to be non-toxic to healthy cells as compared to existing Notch1 inhibitors. Moreover, oral administration of ASR490 abrogated BCSC and BC tumor growth in the in vivo xenograft models. Together our results indicate that ASR490 is a potential therapeutic agent that inhibits BC tumor growth by targeting and abolishing Notch1 signaling in BCSCs and BC cells.

【 授权许可】

Unknown   
Copyright © 2023 Saran, Chandrasekaran, Tyagi, Shukla, Singh, Sharma and Damodaran.