Accumulating evidence suggests that
aspirin has anti-tumorigenic properties in
colorectal cancer (CRC). Herein, we undertook a comprehensive and systematic series of in vivo animal experiments followed by 3D-mathematical modeling to determine the kinetics of
aspirin's anti-
cancer effects on CRC growth. In this study, CRC xenografts were generated using four CRC cell lines with and without PIK3CA mutations and
microsatellite instability, and the animals were administered with various
aspirin doses (0, 15, 50, and 100 mg/kg) for 2 weeks. Cell proliferation, apoptosis and
protein expression were evaluated, followed by 3D-mathematical modeling analysis to estimate cellular division and death rates and their impact on
aspirin-mediated changes on
tumor growth. We observed that
aspirin resulted in a dose-dependent decrease in the cell division rate, and a concomitant increase in the cell death rates in xenografts from all cell lines.
Aspirin significantly inhibited cell proliferation as measured by Ki67 staining (P < 0.05-0.01). The negative effect of
aspirin on the rate of
tumor cell proliferation was more significant in xenograft
tumors derived from PIK3CA mutant versus wild-type cells. A computational model of 3D-tumor growth suggests that the growth inhibitory effect of
aspirin on the
tumor growth kinetics is due to a reduction of
tumor colony formation, and that this effect is sufficiently strong to be an important contributor to the reduction of CRC incidence in
aspirin-treated patients. In conclusion, we provide a detailed kinetics of
aspirin-mediated inhibition of
tumor cell proliferation, which support the epidemiological data for the observed protective effect of
aspirin in CRC patients.