Effect of aspirin on cell proliferation and differentiation of colon adenocarcinoma Caco‐2 cells

Abstract

Several lines of evidence suggest that long-term treatment with non-steroidal anti-inflammatory drugs may reduce the risk of colon cancer and the size and number of colonic polyps in patients with familial adenomatous polyposis. Aspirin has also been shown to inhibit cell proliferation in human tumor cell lines and to induce apoptosis in colonic mucosa of familial polyposis patients. To elucidate the molecular mechanisms of the antiproliferative action of aspirin, we studied the effects of aspirin on cell growth and differentiation of the human colon carcinoma Caco-2 cell line. These cells represent a useful tool for studying the mechanisms involved in the regulation of cell growth and differentiation of intestinal epithelial cells since they spontaneously differentiate into polarized cells, expressing brush border enzymes. We show in this study that aspirin (0.1-10 mM) induces a profound inhibition of cell replication as assessed either by cell counts or thymidine incorporation. Moreover, aspirin concentrations of 5 and 10 mM induce apoptosis, whereas concentrations of 1 and 2 mM do not. The inhibition of growth is associated with a dose-dependent reduction in insulin-like growth factor II mRNA expression and with an increase in sucrase activity (a brush border enzyme) and apolipoprotein A-I mRNA expression, 2 specific markers of the differentiative status of this cell line. Our data thus show that aspirin-dependent inhibition of cell growth is associated with the enterocyte-like differentiation of Caco-2 cells. Int.

Aspirin induces cell death and caspase-dependent phosphatidylserine externalization in HT-29 human colon adenocarcinoma cells

“…However, we found that in B-CLL cells aspirin induces all the typical features of apoptosis, including internucleosomal DNA fragmentation, decrease in DNA content, increase in phosphatidylserine exposure and proteolysis of poly(ADPribose) polymerase (PARP) (Bellosillo et al, 1998). Consistent with our results, it has been reported that aspirin induces apoptosis of colon adenocarcinoma Caco-2 cells (Ricchi et al, 1997), HT-29 cells (Qiao et al, 1998) and crypt cells (Barnes et al, 1998). The apoptotic action of aspirin on B-CLL cells was inhibited by the caspase inhibitor Z-VAD.fmk, demonstrating the involvement of caspases (Bellosillo et al, 1998).…”

IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PGE2 synthesis in Caco-2 human colon carcinoma cells

“…The inhibition of growth was associated with a reduction in IGF-II mRNA expression and with the induction of the enterocyte-like di erentiation of the cells (Ricchi et al, 1997). This ®nding suggested that aspirin by reducing IGF-II expression in turn downregulated cyclo-oxygenase activity and increased apoptosis in Caco-2 cells.…”

“…Aspirin treatment inhibits proliferation of Caco-2 cells and induces the enterocyte-like di erentiation of the cells before they reach con¯uency. These e ects are associated with a dose-dependent reduction in IGF-II mRNA expression (Ricchi et al, 1997).…”

Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy

“…We and others have shown that nonselective and COX-2-selective inhibitors are able to inhibit cell growth and induce apoptosis in colon cancer cells (Elder et al, 1997;Ricchi et al, 1997;Di Popolo et al, 2000).…”