A novel inhibitor targets both Wnt signaling and ATM/p53 in colorectal cancer

For 2017, the estimated lifetime risk of developing colorectal cancer (CRC) was 1 in 22. Even though preventative colonoscopy screening and standard of care surgery, radiation, and chemotherapy have decreased the death rate from CRC, new therapies are needed for metastatic CRC. Here we developed a novel small molecule, compound 2, that inhibited proliferation and viability of human CRC cells (HCT-116, DLD-1, SW480, and 10.1). Compound 2 inhibited cell migration, invasion, and EMT processes and potently increased cell apoptosis in human CRC cells. Compound 2 also modulated mitotic stress signaling, leading to both inhibition of Wnt responsiveness and stabilization and activation of p53 to cause cell cycle arrest. In mouse xenografts, treatment with compound 2 (20 mg/kg/day, i.p.) induced cell death and inhibited tumor growth >4-fold compared to vehicle at day 34. Neither acute cytotoxicity nor toxicity in animals (up to 1000 mg/kg, i.p.) were observed for compound 2. To our knowledge, compound 2 is the first reported potent small molecule that inhibits Wnt/β-catenin signaling, activates p53 signaling regardless of p53 mutation status and binds microtubules without detectable toxicity. Thus, compound 2 offers a novel mechanism of action and a new strategy to treat CRC.

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