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

Cancer Research
Jiongjia ChengJohn R Cashman

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 2, that inhibited proliferation and viability of human colorectal cancer cells (HCT-116, DLD-1, SW480, and 10.1). Compound 2 inhibited cell migration, invasion, and epithelial-mesenchymal transition processes and potently increased cell apoptosis in human colorectal cancer 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 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 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, ...Continue Reading

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Citations

Oct 5, 2019·The Journal of Pharmacology and Experimental Therapeutics·Jiongjia ChengJohn R Cashman
May 16, 2019·EBioMedicine·Simin ZhaoZigang Dong
Dec 29, 2020·Technology in Cancer Research & Treatment·Chuan ChengJianping Wang
May 22, 2021·Cell Chemical Biology·Rebecca L Myers, Peter S Klein
Jun 3, 2021·International Journal of Environmental Research and Public Health·Abhijeet R PatilSourav Roy
Aug 24, 2021·Gastroenterology Research and Practice·Huixia LiJianping Wang

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