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

Abstract

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.

Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy

“…The Notch1 inhibitor ASR490 was reported to suppress the growth of breast cancer stem cells (BCSCs) and breast cancer in xenograft models ( 125 ). ASR490 may represent an attractive therapeutic agent against breast cancer, necessitating further clinical validation.…”

In Vitro and In Vivo Anti-Cancer Activity of Lasiokaurin in a Triple-Negative Breast Cancer Model

“…The migration ability of TNBC was evaluated by wound-healing assays, as previously described [53]. Briefly, MDA-MB-231 cells at a density of 4 × 10 4 cells/well were seeded into both chambers of the culture insert (Ibidi GmbH, Gräfelfing, Germany).…”