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Evidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in -mutant colorectal carcinoma, but not in -wild-type carcinoma. However, whether aspirin directly influences the viability of -mutant colon cancer cells is poorly understood. We conducted experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for -mutant colon cancer cells than for -wild-type colon cancer cells. We measured the anti-proliferative effect of aspirin at physiologic concentrations in seven -mutant and six -wild-type human colon cancer cell lines. After exposure to aspirin, the apoptotic index and cell cycle phase of colon cancer cells were assessed. In addition, the effect of aspirin was examined in parental SW48 cells and SW48 cell clones with individual knock-in mutations of either c.3140A>G (p.H1047R) or c.1633G>A (p.E545K). Aspirin induced greater dose-dependent loss of cell viability in -mutant cells than in -wild-type cells after treatment for 48 and 72 hours. Aspirin treatment also led to higher proportions of apoptotic cells and G0/G1 phase arrest in -mutant cells than in -wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a mutation, either c.3140A>G (p.H1047R) or c.1633G>A (p. E545K), resulted in a more significant loss of cell viability compared to wild-type controls. Our findings indicate that aspirin causes cell cycle arrest, induces apoptosis, and leads to loss of cell viability more profoundly in -mutated colon cancer cells than in -wild-type colon cancer cells. These findings support the use of aspirin to treat patients with -mutant colon cancer.