Novel Sulindac Derivatives for Colon Cancer Chemoprevention

Summary

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

Top Publications

  1. pmc A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity
    Gary A Piazza
    Drug Discovery and Development Divisions, Southern Research Institute, Birmingham, Alabama 35205, USA
    Cancer Prev Res (Phila) 2:572-80. 2009
  2. ncbi Synthesis of novel peptidyl adenosine antibiotic analogs
    Omar Moukha-chafiq
    a Southern Research Institute, Drug Discovery Division, Birmingham, AL 35205, USA
    Nucleosides Nucleotides Nucleic Acids 33:53-63. 2014
  3. pmc 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
  4. pmc Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling
    Nan 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
  5. pmc A novel quinoline derivative that inhibits mycobacterial FtsZ
    Bini Mathew
    Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
    Tuberculosis (Edinb) 93:398-400. 2013
  6. pmc MicroRNA and cancer chemoprevention
    Bin Yi
    Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Ave, Mobile, AL 36604, USA
    Cancer Prev Res (Phila) 6:401-9. 2013
  7. pmc A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy
    Evrim Gurpinar
    Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
    Mol Cancer Ther 12:663-74. 2013
  8. pmc New NSAID targets and derivatives for colorectal cancer chemoprevention
    Heather N Tinsley
    Department of Biology, University of Montevallo, Montevallo, AL, USA
    Recent Results Cancer Res 191:105-20. 2013
  9. pmc A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity
    Jason D Whitt
    Department of Pharmacology, The University of Alabama at Birmingham, Birmingham, AL, USA
    Cancer Prev Res (Phila) 5:822-33. 2012
  10. pmc Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells
    Heather N Tinsley
    Drug Discovery Division, Southern Research Institute, Birmingham, Alabama, USA
    Cancer Prev Res (Phila) 4:1275-84. 2011

Research Grants

Detail Information

Publications16

  1. pmc A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity
    Gary 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...
  2. ncbi Synthesis of novel peptidyl adenosine antibiotic analogs
    Omar 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. ..
  3. pmc 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...
  4. pmc Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling
    Nan 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...
  5. pmc A novel quinoline derivative that inhibits mycobacterial FtsZ
    Bini Mathew
    Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
    Tuberculosis (Edinb) 93:398-400. 2013
    ....
  6. pmc MicroRNA and cancer chemoprevention
    Bin Yi
    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...
  7. pmc A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy
    Evrim 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...
  8. pmc New NSAID targets and derivatives for colorectal cancer chemoprevention
    Heather 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...
  9. pmc A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity
    Jason 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...
  10. pmc Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells
    Heather 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...
  11. pmc Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition
    Heather 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...
  12. ncbi A novel sulindac derivative lacking cyclooxygenase-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model
    Yong 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...
  13. pmc 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 G
    Heather 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...

Research Grants30

  1. The Sphingolipid Pathway in Colon Cancer Chemoprevention
    Toshihiko Kawamori; Fiscal Year: 2013
    ..abstract_text> ..