Fish Oil Modulation of Tumor Inflammation

Summary

Principal Investigator: N Joseph Espat
Abstract: The primary purpose of this mentored award is to prepare the applicant for a career as an independent physician scientist. The applicant proposes to acquire additional skills in cell biology and molecular analysis in the context of a project that is directly relevant to his clinical specialty. The-long term goals are: 1) to investigate the mechanism(s) and define the relationship between tumor related inflammation and cancer associated cachexia; and 2) to develop safe and effective anti-inflammatory treatment strategies for patients with progressive malignancy using (nutritional) eicosapentaenoic acid, (EPA)) and/or (pharmacologic) selective cyclo-oxygenase-II (COX-II) inhibitor agents. Anorexia, weight loss and the catabolism of lean body mass define the clinical syndrome of cancer-associated cachexia. Preventing or delaying cachexia is a clinically significant goal, since improved outcome and survival for cancer patients has been consistently demonstrated to parallel the preservation of lean body mass. 1-4 Clinical and experimental evidence from our lab and others supports the use of EPA as an anti-inflammatory therapy. EPA is a w-3 fatty acid that may attenuate the production of pro-inflammatory cytokines, growth factors and inflammatory mediators, in response to inflammatory stimuli, however the mechanism(s) remain to be defined. Hypothesis: EPA alone or in combination with COX-II inhibitors attenuate the tumor-related inflammation of progressive malignancy. To test this hypothesis we will use the in vitro RAW 264-7 cell culture model and the well-established rodent model of progressive malignancy resulting in cancer-cachexia, the methyl-cholanthrene (MCA) fibrosarcoma, with the following specific aims. AIM1: To evaluate in vitro EPA and/or COX-II inhibition of macrophage TNF-alpha, IL-1beta, prostaglandin E2, COX-II enzyme production, NF-kB activity and apoptosis. AIM 2: To evaluate in vivo EPA and/or COX-II inhibition therapies of tumor-related TNF-alpha, IL-1beta, prostaglandin E2, COX-Il enzyme production, NF-kB activity, apoptosis and regulation of the ubiquitin proteasome proteolytic pathway in response to progressive non-metastasizing malignancy.
Funding Period: 2002-09-01 - 2007-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Omega-3 fatty acids: investigations from cytokine regulation to pancreatic cancer gene suppression
    Cherif Boutros
    Department of Hepatobiliary and Surgical Oncology, Roger Williams Medical Center, 825 Chalkstone Ave, Prior 4, Providence, RI 02908, USA
    Arch Surg 145:515-20. 2010
  2. ncbi Experimental studies defining omega-3 fatty acid antiinflammatory mechanisms and abrogation of tumor-related syndromes
    Tricia A Babcock
    Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA
    Nutr Clin Pract 20:62-74. 2005
  3. ncbi Understanding clinical issues in postoperative nutrition after pancreaticoduodenectomy
    Witold Zgodzinski
    2nd Department of General Surgery, Skubiszewski Medical University of Lublin, Poland
    Nutr Clin Pract 20:654-61. 2005
  4. ncbi A priori dietary omega-3 lipid supplementation results in local pancreatic macrophage and pulmonary inflammatory response attenuation in a model of experimental acute edematous pancreatitis (AEP)
    Suhail Sharif
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    JPEN J Parenter Enteral Nutr 30:271-6. 2006
  5. ncbi G2/M cell-cycle arrest and apoptosis by n-3 fatty acids in a pancreatic cancer model
    Thomas Dekoj
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Surg Res 139:106-12. 2007
  6. ncbi Attenuation of iNOS in an LPS-stimulated macrophage model by omega-3 fatty acids is independent of COX-2 derived PGE2
    Anthony Razzak
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Surg Res 145:244-50. 2008
  7. pmc Lipopolysaccharide-stimulated RAW 264.7 macrophage inducible nitric oxide synthase and nitric oxide production is decreased by an omega-3 fatty acid lipid emulsion
    Christopher Aldridge
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
    J Surg Res 149:296-302. 2008

Detail Information

Publications7

  1. ncbi Omega-3 fatty acids: investigations from cytokine regulation to pancreatic cancer gene suppression
    Cherif Boutros
    Department of Hepatobiliary and Surgical Oncology, Roger Williams Medical Center, 825 Chalkstone Ave, Prior 4, Providence, RI 02908, USA
    Arch Surg 145:515-20. 2010
    ..An increased emphasis has been placed on the potential for diet and dietary supplements to serve as modulators of host response to disease, injury, and infection...
  2. ncbi Experimental studies defining omega-3 fatty acid antiinflammatory mechanisms and abrogation of tumor-related syndromes
    Tricia A Babcock
    Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA
    Nutr Clin Pract 20:62-74. 2005
    ..In this review, we discuss the recent progress made in our laboratory on defining the mechanisms of omega-3 fatty acids activity...
  3. ncbi Understanding clinical issues in postoperative nutrition after pancreaticoduodenectomy
    Witold Zgodzinski
    2nd Department of General Surgery, Skubiszewski Medical University of Lublin, Poland
    Nutr Clin Pract 20:654-61. 2005
    ..It is the aim of this report to provide the reader with an overview of the procedure, common postoperative nutrition issues, and available interventions...
  4. ncbi A priori dietary omega-3 lipid supplementation results in local pancreatic macrophage and pulmonary inflammatory response attenuation in a model of experimental acute edematous pancreatitis (AEP)
    Suhail Sharif
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    JPEN J Parenter Enteral Nutr 30:271-6. 2006
    ....
  5. ncbi G2/M cell-cycle arrest and apoptosis by n-3 fatty acids in a pancreatic cancer model
    Thomas Dekoj
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Surg Res 139:106-12. 2007
    ..e., TNF-alpha, IL-10 and PGE(2)) in many cell lines. However, mechanisms of anti-proliferative effects have not been clearly defined...
  6. ncbi Attenuation of iNOS in an LPS-stimulated macrophage model by omega-3 fatty acids is independent of COX-2 derived PGE2
    Anthony Razzak
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    J Surg Res 145:244-50. 2008
    ..Selective COX-2 inhibitor (L-748,731) experiments and separate PGE2 repletion studies were used to test this hypothesis...
  7. pmc Lipopolysaccharide-stimulated RAW 264.7 macrophage inducible nitric oxide synthase and nitric oxide production is decreased by an omega-3 fatty acid lipid emulsion
    Christopher Aldridge
    Department of Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
    J Surg Res 149:296-302. 2008
    ..We hypothesized that pretreating with an omega-3 FA lipid emulsion would decrease the production of NO in macrophages and that this effect would occur through alterations in inducible nitric oxide synthetase (iNOS)...