Genomes and Genes
Novel Sulindac Derivatives for Colon Cancer Chemoprevention
Principal Investigator: Robert C Reynolds
Abstract: Abstract 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.
Funding Period: 2008-01-01 - 2013-12-31
more information: NIH RePORT
- A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activityGary A Piazza
Drug Discovery and Development Divisions, Southern Research Institute, Birmingham, Alabama 35205, USA
Cancer Prev Res (Phila) 2:572-80. 2009..These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy...
- Synthesis of novel peptidyl adenosine antibiotic analogsOmar Moukha-chafiq
a Southern Research Institute, Drug Discovery Division, Birmingham, AL 35205, USA
Nucleosides Nucleotides Nucleic Acids 33:53-63. 2014..No marked anticancer and antimalaria activity was noted on preliminary cellular testing; however these analogs should be useful candidates for other types of biological activity. ..
- NSAIDs inhibit tumorigenesis, but how?Evrim Gurpinar
Authors Affiliations Department of Pharmacology and Toxicology Department of Pathology, The University of Alabama at Birmingham, Birmingham and Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
Clin Cancer Res 20:1104-13. 2014..Here, we review the evidence for COX-independent mechanisms and discuss progress toward identifying alternative targets and developing NSAID derivatives that lack COX-inhibitory activity but have improved antineoplastic properties...
- Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signalingNan Li
Corresponding Author Gary A Piazza, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Suite 3029, Mobile, AL 36604
Mol Cancer Ther 12:1848-59. 2013..These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP-degrading isozymes...
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Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
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Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Ave, Mobile, AL 36604, USA
Cancer Prev Res (Phila) 6:401-9. 2013..In this review, we summarize recent publications that highlight a potentially important role of miRNAs in cancer chemoprevention research...
- A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagyEvrim Gurpinar
Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Mol Cancer Ther 12:663-74. 2013..This unique mechanism of action, along with its increased potency and lack of COX inhibition, supports the development of SSA or related analogs for the prevention and/or treatment of lung cancer...
- New NSAID targets and derivatives for colorectal cancer chemopreventionHeather N Tinsley
Department of Biology, University of Montevallo, Montevallo, AL, USA
Recent Results Cancer Res 191:105-20. 2013..Here, we review several promising mechanisms that are being targeted to develop safer and more efficacious NSAID derivatives for colon cancer chemoprevention...
- A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activityJason D Whitt
Department of Pharmacology, The University of Alabama at Birmingham, Birmingham, AL, USA
Cancer Prev Res (Phila) 5:822-33. 2012..We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention...
- Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cellsHeather N Tinsley
Drug Discovery Division, Southern Research Institute, Birmingham, Alabama, USA
Cancer Prev Res (Phila) 4:1275-84. 2011..We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention...
- Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibitionHeather N Tinsley
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA
Cancer Prev Res (Phila) 3:1303-13. 2010..These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs...
- A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate modelYong Zhang
Hormel Institute, University of Minnesota, Austin, 55912, USA
Cancer Prev Res (Phila) 3:885-95. 2010..Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis...
- Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase GHeather N Tinsley
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35205, USA
Mol Cancer Ther 8:3331-40. 2009..These data suggest that PDE5 inhibition is responsible for the breast tumor cell growth-inhibitory and apoptosis-inducing activity of SS and may contribute to the chemopreventive properties of sulindac...
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