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- W2741505875 abstract "We recently showed that two different ALDH+ and CD44+/CD24-/low breast cancer stem cells (BSCSs) exhibited stem cell characteristics that include self-renewal, extensive proliferation, the ability to form non-adherent spherical clusters, chemotherapy resistance and high Notch1 expression. We have identified a compound compound: 6-(3-methylbut-2-enyl) coumestrol (Pso) and treatment with Pso resulted in growth inhibition and an EMT phenotype in both BCSCs and BC cells. Oral Pso administration at physiologically achievable doses (25 mg/kg/BW) suppressed the growth of BCSCs and BC xenografts without toxicity. In the current studies, we identified several novel Pso-derived analogs that may be more potent than the parent compound. One such compound, 1-methoxyphaseollidin (1MP), obtained via three main functional group changes: (i) translocation of the isoprenyl moiety from the phenyl ring fused to the pyran ring (as in Pso) to the phenyl ring adjacent to the furan ring, (ii) removal of the carbonyl group from the pyran ring, and (iii) introduction of a methoxy group at the 1-position, inhibited Notch1 activity and growth of both BSCS and BC cells at nM concentration (IC50: 300nM), which is 100 times more potently than Pso in cell culture models. Molecular studies suggest that 1MP inhibits Notch signaling pathways (Hes1, Hey1 and Presenilin) in both BCSC and BC cells. Further, downregulation of AKT signaling (pAKT (S473), p65 and BCl-2 were seen in 1MP treated cells. Docking studies suggest that 1MP binds outside of the catalytic unit of γ-secretase and induces a conformational change, resulting in Notch1 inhibition in both BCSCs and BC cells. More importantly, administration of 1MP significantly inhibited the growth of BCSC and BC tumors without causing gastrointestinal toxicity in tumor-bearing mice. HE 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2903. doi:10.1158/1538-7445.AM2017-2903" @default.
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- W2741505875 date "2017-07-01" @default.
- W2741505875 modified "2023-09-22" @default.
- W2741505875 title "Abstract 2903: 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells" @default.
- W2741505875 doi "https://doi.org/10.1158/1538-7445.am2017-2903" @default.
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