A Novel Inhibitor Targets Both Wnt Signaling and ATM/p53 in Colorectal Cancer.

Abstract

For 2017, the estimated lifetime risk of developing colorectal cancer was 1 in 22. Even though preventative colonoscopy screening and standard-of-care surgery, radiation, and chemotherapy have decreased the death rate from colorectal cancer, new therapies are needed for metastatic colorectal cancer. Here, we developed a novel small molecule, compound <b>2</b>, that inhibited proliferation and viability of human colorectal cancer cells (HCT-116, DLD-1, SW480, and 10.1). Compound <b>2</b> inhibited cell migration, invasion, and epithelial-mesenchymal transition processes and potently increased cell apoptosis in human colorectal cancer cells. Compound <b>2</b> 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 <b>2</b> (20 mg/kg/day, i.p.) induced cell death and inhibited tumor growth more than four-fold compared with vehicle at day 34. Neither acute cytotoxicity nor toxicity in animals (up to 1,000 mg/kg, i.p.) were observed for compound <b>2</b> To our knowledge, compound <b>2</b> 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 <b>2</b> offers a novel mechanism of action and a new strategy to treat colorectal cancer.<b>Significance:</b> These findings identify a potent small molecule that may be therapeutically useful for colon cancer that works by inhibiting Wnt/β-catenin signaling, activating p53, and binding microtubules without detectable toxicity. <i>Cancer Res; 78(17); 5072-83. ©2018 AACR</i>.