Nonsteroidal anti-inflammatory drugs (NSAIDs) display striking antineoplastic activity, although toxicity resulting from cyclooxygenase (COX) inhibition and incomplete protection from disease progression limits their use for cancer chemoprevention. Preliminary studies suggest that the mechanism for the chemopreventive activity of a highly efficacious NSAID, sulindac, does not require the inhibition of COX-1 or -2 and that cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition is responsible for its tumor cell growth inhibitory activity. We hypothesize that it is feasible to chemically modify sulindac to block COX inhibitory activity, while enhancing tumor cell growth inhibitory activity by increasing selectivity for cGMP PDE. In support of this hypothesis, we have synthesized a prototypic amide derivative of sulindac sulfide that does not inhibit COX-1 or -2, yet displays high potency to inhibit colon tumor cell growth and cGMP PDE in vitro. Sulindac sulfide amide (SSA) displayed adequate oral bioavailability and appeared to be less toxic than sulindac in mice. Using a xenograft model involving human colon tumor cells, SSA displayed comparable in vivo antitumor efficacy as sulindac, albeit at high dosages. These studies demonstrate the feasibility of uncoupling the COX inhibitory activity from the growth inhibitory activity of sulindac and supports further research to develop additional derivatives that are more potent and/or bioavailable than SSA. The following specific aims are proposed: 1) prepare a series of sulindac analogs to optimize for potency, selectivity, and oral bioavailability, 2) evaluate in vitro activity, 3) determine the mechanism of action and identify the target cGMP PDE isozyme, and 4) evaluate in vivo chemopreventive efficacy. Our goals are to identify a safe and efficacious derivative of sulindac for cancer chemoprevention and to critically test the hypothesis that cGMP PDE is a target for cancer chemoprevention. This multidisciplinary research proposal is anticipated to result in a new drug candidate for cancer chemoprevention, and in particular, patients with familial or sporadic adenomatous polyposis who are at high risk of disease progression. Project Narrative Nonsteroidal anti-inflammatory drugs (NSAIDs) display striking cancer chemopreventive activity, although toxicity resulting from cyclooxygenase (COX) inhibition and incomplete efficacy limits their clinical use for patients at moderate to high risk of disease progression. Preliminary studies suggest that the mechanism for the antineoplastic activity of sulindac does not require COX inhibition and that cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition is responsible for its tumor cell growth inhibitory activity. We hypothesize that it is feasible to chemically modify sulindac to block COX inhibitory activity, while enhancing tumor cell growth inhibitory activity by increasing selectivity for cGMP PDE. Our primary goal is to identify a novel sulindac derivative as a clinical candidate for patients with either familial or sporadic adenomatous polyps who are at high risk of disease progression. A secondary goal is to critically test the hypothesis that cGMP PDE is a target for cancer chemoprevention and involved in carcinogenesis. This multidisciplinary research proposal may lead to a novel strategy for colon cancer chemoprevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131378-05
Application #
8207302
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Lubet, Ronald A
Project Start
2008-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$670,313
Indirect Cost
$327,184
Name
Southern Research Institute
Department
Type
DUNS #
006900526
City
Birmingham
State
AL
Country
United States
Zip Code
35205
Mathew, Bini; Hobrath, Judith V; Connelly, Michele C et al. (2017) Diverse amide analogs of sulindac for cancer treatment and prevention. Bioorg Med Chem Lett 27:4614-4621
Keeton, Adam B; Salter, E Alan; Piazza, Gary A (2017) The RAS-Effector Interaction as a Drug Target. Cancer Res 77:221-226
Mathew, Bini; Hobrath, Judith V; Lu, Wenyan et al. (2017) Synthesis and preliminary assessment of the anticancer and Wnt/?-catenin inhibitory activity of small amide libraries of fenamates and profens. Med Chem Res 26:3038-3045
Zhu, Bing; Lindsey, Ashley; Li, Nan et al. (2017) Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking ?-catenin and MAPK signaling. Oncotarget 8:69264-69280
Piazza, Gary A (2017) Validation of PDE5 as a Chemoprevention Target. Cancer Prev Res (Phila) 10:373-376
Yi, Bin; Chang, Hong; Ma, Ruixia et al. (2016) Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGF?/miR-21 signaling. Oncotarget 7:7979-92
Lee, Kevin; Lindsey, Ashley S; Li, Nan et al. (2016) ?-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 7:5353-65
Prasain, Jeevan K; Rajbhandari, Rajani; Keeton, Adam B et al. (2016) Metabolism and growth inhibitory activity of cranberry derived flavonoids in bladder cancer cells. Food Funct 7:4012-4019
Li, N; Lee, K; Xi, Y et al. (2015) Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and ?-catenin-dependent TCF transcriptional activity. Oncogene 34:1499-509
Elhady, Ahmed K; Sigler, Sara C; Noureldin, Nazih et al. (2015) Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential Phosphodiesterase Inhibitors. Sci Pharm 84:428-446

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