Abstract
Evidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in PIK3CA-mutant colorectal carcinoma, but not in PIK3CA-wild-type carcinoma. However, whether aspirin directly influences the viability of PIK3CA-mutant colon cancer cells is poorly understood. We conducted in vitro experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for PIK3CA-mutant colon cancer cells than for PIK3CA-wild-type colon cancer cells. We measured the anti-proliferative effect of aspirin at physiologic concentrations in seven PIK3CA-mutant and six PIK3CA-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 PIK3CA mutations of either c.3140A>G (p.H1047R) or c.1633G>A (p.E545K). Aspirin induced greater dose-dependent loss of cell viability in PIK3CA-mutant cells than in PIK3CA-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 PIK3CA-mutant cells than in PIK3CA-wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a PIK3CA 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 PIK3CA-mutated colon cancer cells than in PIK3CA-wild-type colon cancer cells. These findings support the use of aspirin to treat patients with PIK3CA-mutant colon cancer.
Highlights
Colorectal cancer is the second leading cause of cancer-related deaths in the U.S [1], and the prognosis for individuals with advanced colorectal cancer remains poor [2, 3]
The U.S Preventive Services Task Force (USPSTF) recommended the use of aspirin for prevention of colorectal cancer in individuals at a 10% increased risk for cardiovascular disease compared with the general population [17], while cautioning against the potential harms associated with regular aspirin use including gastrointestinal pain and bleeding [18]
To test the hypothesis that aspirin’s anti-cancer effects might differ by PIK3CA mutation status, we investigated the anti-proliferative activity of aspirin at physiologically attainable concentrations in seven PIK3CA-mutant and six PIK3CA-wild-type colon cancer cell lines (Table 1) using the 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium inner salt (MTS) assay
Summary
Colorectal cancer is the second leading cause of cancer-related deaths in the U.S [1], and the prognosis for individuals with advanced colorectal cancer remains poor [2, 3]. Accumulating evidence indicates that colorectal cancer is a heterogeneous group of diseases, and that responsiveness to treatment varies from patient to patient [4,5,6,7]. This heterogeneity necessitates precision medicine approaches that take tumor molecular characteristics into account in order to predict an individual’s response to a specific agent. The U.S Preventive Services Task Force (USPSTF) recommended the use of aspirin for prevention of colorectal cancer in individuals at a 10% increased risk for cardiovascular disease compared with the general population [17], while cautioning against the potential harms associated with regular aspirin use including gastrointestinal pain and bleeding [18]. It is of particular interest to identify subgroups of individuals who are most likely to benefit from aspirinbased therapeutic strategies through the development of informative tumor biomarkers [14]
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