Masters Thesis

Lh14e, a Novel Beta-catenin Protein Inhibitor and Cell Cycle Arresting Drug, Outperforms Other Wnt Mimetics.

LH14E is a novel small molecule, which may induce cell cycle arrest by inhibiting the Wnt/β-catenin signaling pathway. The canonical Wnt signaling pathway is important in cancer, developmental biology, and normal cellular functions. Despite extensive efforts, the field has yet to successfully develop effective small-molecule that can inhibit progression of β-catenin-related cancers in the clinic. In this study, I demonstrate a new cell cycle arrest compound which acts on the β-catenin signaling pathway. The small-molecule LH14E reduced β-catenin protein levels by 60% and inhibited β-catenin transcriptional activity by 37% in HeLa human cervical cancer cells. Under treatment with LH14E, CCND1 gene expression was reduced by 39%. LH14E also reduced cell numbers to 60% of control, indicating a reducing in the rate of cell proliferation. The effects of LH14E on the cell growth rate in serum-free medium was comparable to Cisplatin and Mitomycin C, two well-studied first-line chemotherapy drugs. I also found evidence that LH14E reduced mitochondrial activity in HeLa cells. The evidence presented here supports LH14E’s potential as a cancer therapeutic and prompts further investigation of LH14E in vivo.

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