Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells

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.

Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology

“…Although each individual study might not have adequate statistical power, particularly for PIK3CA-mutant cases, most of these studies (but not all; see 54, 60) had similar findings (61)(62)(63)(64). Moreover, in vitro experimental studies showed stronger antitumor effects of aspirin against PIK3CA-mutant colon and breast cancer cells compared with PIK3CA wild-type cells (65)(66)(67). These lines of evidence are consistent with aspirin having specific effects on PIK3CA-mutant colorectal carcinomas ( Figure 5), and they provide a rationale for designing clinical trials that assess the therapeutic effects of aspirin and the predictive values of tumor biomarkers (33,50,68,69).…”

Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells

“…Aspirin may suppress colon cancer cell growth and induce apoptosis by blocking the PI3K pathway. In vitro studies have shown that aspirin induces the apoptosis of colon cancer cell lines bearing PI3KC mutations (3140A > G or 1633G > A) and this effect was clearly more pronounced in these cells than in colon cancer cells with the PI3KC wild-type [ 107 ]. In line with this hypothesis, a recent clinical study based on the analysis of a large set of patients clearly showed that aspirin administration resulted in an improvement of survival selectively among patients with PI3KCA mutations [ 108 ].…”

Acetylsalicylic Acid and its Potential for Chemoprevention of Colorectal Carcinoma

“…Lze odůvodněně předpokládat, že minimálně zčásti jsou tyto mechanizmy podmíněny snížením koncentrace PGE2, což úzce souvisí se všemi výše uvedenými důsledky. V buněčných liniích odvozených od CRC způsobuje ASA zejména u buněk s mutací v PIK3CA zástavu buněčného cyklu a indukci apoptózy [23]. Dále je popsáno zvýšení hladiny "mismatch repair" proteinů [24].…”