Aspirin-Induced Chemoprevention and Response Kinetics Are Enhanced by PIK3CA Mutations in Colorectal Cancer Cells.

This study was designed to determine how aspirin influences the growth kinetics and characteristics of cultured colorectal cancer cells that harbor a variety of different mutational backgrounds, including - and -activating mutations, and the presence or absence of microsatellite instability. Colorectal cancer cell lines (HCT116, HCT116 + Chr3/5, RKO, SW480, HCT15, CACO2, HT29, and SW48) were treated with pharmacologically relevant doses of aspirin (0.5-10 mmol/L) and evaluated for proliferation and cell-cycle distribution. These parameters were fitted to a mathematical model to quantify the effects and understand the mechanism(s) by which aspirin modifies growth in colorectal cancer cells. We also evaluated the effects of aspirin on key G-G cell-cycle genes that are regulated by the PI3K-Akt pathway. Aspirin decelerated growth rates and disrupted cell-cycle dynamics more profoundly in faster growing colorectal cancer cell lines, which tended to be mutants. Additionally, microarray analysis of 151 colorectal cancer cell lines identified important cell-cycle regulatory genes that are downstream targets of PIK3 and were also dysregulated by aspirin treatment ( and ). Our study demonstrated what clinical trials have only speculated, that -mutant colorectal cancers are more sensitive to aspirin. Aspirin inhibited cell growth in all colorectal cancer cell lines regardless of mutational background, but the effects were exacerbated in cells with mutations. Mathematical modeling combined with bench science revealed that cells with -mutations experience significant G-G arrest and explains why patients with mutant colorectal cancers may benefit from aspirin use after diagnosis. .