Nonsteroidal anti-inflammatory drugs and the induction of apoptosis in colon cells: Evidence for PHS-dependent and PHS-independent mechanisms

NSAIDS are potent chemopreventive agents for colon cancer. Although their mechanism of action is unknown, it probably relates to their modulation of colon epithelial cell kinetics, i.e. apoptosis and/or cell proliferation. NSAIDs are pleiotropic in their biochemical activities; their best known effect is inhibition of prostaglandin H synthase (PHS), the enzyme catalyzing the biosynthesis of prostaglandins. Current data appear to lead to two conflicting conclusions. One body of data indicates that PHS is important in induction of apoptosis and colon carcinogenesis and that its inhibition by NSAIDs is required for induction of apoptosis and their overall chemopreventive effect. Another set of data indicates that NSAIDs may induce apoptosis and prevent colon cancer without inhibiting the activity of PHS. Both sides of this argument are presented and discussed. This apparent contradiction may be resolved if one accepts that both mechanisms are correct but that they act on different steps of this multistep process.