SC-560, a strucutral analogue of celecoxib, induces growth inhibition in a wide range of human cancer cells in a cyclooxygenase (COX)-independent manner. Since SC-560 suppresses the growth of cancer cells mainly by inducing cell cycle arrest, we sought to examine the role of p21CIP1, a cell cycle regulator protein, in the cellular response against SC-560 by using p21(+/+)and p21(-/-)isogenic HCT116 colon carcinoma cells. In HCT116 (p21(+/+)) cells, SC-560 dose-dependently induced growth inhibition and cell cycle arrest at the G1 phase without significant apoptosis induction. SC-560-induced cell cycle arrest was accompanied by upregulation of p21CIP1. However, the extent of SC-560-induced accumulation at the G1 phase was approximately equal in the p21(+/+)and the p21(-/-)cells. Nonetheless, the growth inhibition by SC-560 was increased in p21(-/-)cells than p21(+/+)cells. SC-560-induced reactive oxygen species (ROS) generation did not differ between p21(+/+)and p21(-/-)cells but the subsequent activaton of apoptotic caspase cascade was more pronounced in p21(-/-)cells compared with p21(+/+)cells. These results suggest that p21CIP1 blocks the SC-560-induced apoptotic response of HCT116 cells. SC-560 combined with other therapy that can block p21 CIP1 expression or function may contribute to the effective treatment of colon cancer.
Reactive Oxygen Species/metabolism ; Pyrazoles/*pharmacology ; Mutation ; Immunoblotting ; Humans ; HCT116 Cells ; Genotype ; Flow Cytometry ; Dose-Response Relationship, Drug ; Cyclooxygenase Inhibitors/pharmacology ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism/*physiology ; Colonic Neoplasms/genetics/metabolism/pathology ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; Cell Differentiation/drug effects ; Cell Cycle Proteins/metabolism ; Cell Cycle/drug effects ; Apoptosis/drug effects ; Antineoplastic Agents/pharmacology