Abstract
Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme-specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin-mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared with normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 (COX-2)–selective inhibitors display promising chemopreventive efficacy, especially for colorectal cancer
NSAID inhibition of colon tumor cell growth correlates with cGMP PDE inhibition To determine whether cGMP PDE represents a potential COX-independent target responsible for the antineoplastic activity of sulindac, we compared the non–COX-inhibitory sulfone and sulfoxide forms of the drug with the COX-1– and COX-2–inhibitory sulfide metabolite, the highly selective COX-2 inhibitor rofecoxib, and the COX-1–selective inhibitor indomethacin
The highly potent and specific COX-2 inhibitor rofecoxib was unable to inhibit colon tumor cell proliferation or cGMP PDE activity. These results show that the potency for cGMP PDE inhibition, but not the potency for COX-1 or COX-2 inhibition, is closely associated with colon tumor cell growth–inhibitory potency among sulindac and its metabolites
Summary
Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 (COX-2)–selective inhibitors display promising chemopreventive efficacy, especially for colorectal cancer. Studies have shown that the non–COX-inhibitory sulfone metabolite of the NSAID sulindac can inhibit human colon tumor cell growth and induce apoptosis in vitro [7, 8]. The non–COX-inhibitory sulfone metabolite is irreversibly generated by oxidation of either the sulfide or the sulfoxide form in the liver Both metabolites have been shown to inhibit tumor cell growth and induce apoptosis [7, 8], only the sulfone metabolite has been studied with regard to cGMP PDE inhibition in colon tumor cells [12]. We characterize the cGMP PDE–inhibitory activity of SS and other NSAIDs and provide evidence that the tumor cell growth–inhibitory and apoptosis-inducing activity of SS is the result of cGMP elevation caused by selective inhibition of the PDE5 isozyme, which is overexpressed in colon tumor cells compared with normal colonocytes
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