? ? Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac display striking chemoprotective activity, for example, to cause the regression of precancerous lesions in patients with either familial or sporadic adenomatous polyposis. Unfortunately, toxicity resulting from cyclooxygenase (COX) inhibition and the depletion of physiologically important prostaglandins limits the utility of NSAIDs and COX-2 selective inhibitors for chemoprevention. Previous studies suggest that the mechanism responsible for the antineoplastic activity of NSAIDs may involve a COX-independent mechanism. Further mechanistic studies are thus warranted to identify critical off-target effects of NSAIDs that may lead to new strategies for cancer chemoprevention. Recently, we have made two key observations which lead us to conclude that it is feasible to develop safer and more efficacious sulindac derivatives for individuals with familial or sporadic adenomatous polyposis without disrupting prostaglandin synthesis. First, we have synthesized a novel sulindac sulfide amide (SSA) that displays reduced COX-1 and COX-2 inhibitory activity compared to sulindac sulfide (SS), yet appreciable greater potency to inhibit the growth of cultured human colon tumor cells. Secondly, we have found that SS inhibits phosphodiesterase (PDE) at concentrations comparable to those required to inhibit tumor cell growth and that SSA also inhibits PDE but with greater potency, despite reduced COX binding. These studies support further testing of SSA and suggest that PDE inhibition and cyclic nucleotide elevation may be an important target and pathway to exploit for future drug discovery efforts. Our overall goal is to use SSA as a molecular probe to study the mechanism responsible for the chemopreventive properties of NSAIDs.
The specific aims are to: 1) characterize the growth inhibitory effects of SSA using cultured human colon tumor cell lines, 2) identify the specific PDE isozyme(s) responsible for the growth inhibitory activity of SSA, and 3) determine chemopreventive efficacy of SSA in the ApcMin mouse model of familial adenomatous polyposis. The proposed studies are anticipated to support SSA as a preclinical candidate for further safety and efficacy evaluation and may lead to a novel molecular target that can be used for high throughput screening of large chemical repositories to identify additional leads for colon cancer chemoprevention. ? ? ?
| Tinsley, Heather N; Gary, Bernard D; Thaiparambil, Jose et al. (2010) Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev Res (Phila) 3:1303-13 |
| Piazza, Gary A; Keeton, Adam B; Tinsley, Heather N et al. (2009) A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity. Cancer Prev Res (Phila) 2:572-80 |
