Colon Tumor Cell Growth–Inhibitory Activity of Sulindac Sulfide and Other Nonsteroidal Anti-Inflammatory Drugs Is Associated with Phosphodiesterase 5 Inhibition

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. Cancer Prev Res; 3(10); 1303-13. ©2010 AACR.

Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia

“…With regards to CRC, non-steroidal anti-inflammatory drugs (NSAIDs) decrease mortality rate and inhibit de novo disease development. The exact mechanism by which NSAIDs exert their anticarcinogenic effect is not completely understood [3, 4]. Investigators attribute part of the anticancer activity of NSAIDs to their inhibition of the cyclooxygenase (COX) enzymes, leading to a decrease in activity of prostaglandins and cyclic adenosine monophosphate (cAMP) [5, 6].…”

cGMP signaling as a target for the prevention and treatment of breast cancer

“…While the primary target of NSAIDs is the COX enzyme family, numerous studies demonstrate the target promiscuity of these drugs and their ability to activate cGMP signaling [11][12][13][14][15][48][49][50][51][52]. As was seen with the PDE5 selective inhibitors, many of the NSAIDs, including metabolites that lack COX-inhibitory activity, lead to cGMP signaling activation and subsequent apoptosis in human breast cancer cells [14,15,53].…”

Phosphodiesterase Type 5 as a Candidate Therapeutic Target in Cancers

“…Sildenafil was also effective against Waldenstrom's Macroglobulinemia (WM), an . Exisulind (sulindac sulfone, aptosyn), a derivative of the oral anti-inflammatory drug sulindac, and its higher affinity analogs have been shown to act as direct inhibitors of PDE5 activity, without affecting prostaglandin levels, or cyclooxygenase-inducing actions [6,8,21,26,65,[67][68][69]. Indeed, exisulind selectively exerted pro-apoptotic and anti-proliferative effects in various human prostate, colon, and breast cancer cells with minimal effects on normal epithelial cells.…”

“…Indeed, exisulind selectively exerted pro-apoptotic and anti-proliferative effects in various human prostate, colon, and breast cancer cells with minimal effects on normal epithelial cells. Its effects on cell growth were associated with inhibition of b-catenin-mediated transcriptional activity and consequent suppression of the synthesis of target genes, such as cyclin D1 and survivin [21,68]. This drug has also been demonstrated to inhibit human prostate [70] and lung [6] cancer growth in animal models by inducing apoptotic events.…”