Facebook Pixel Code
About Sickkids
About SickKids

Cecil Pace-Asciak, PhD

Research Institute
Senior Scientist Emeritus
Translational Medicine

University of Toronto
Professor
Pharmacology


Phone: 416-813-5755
Fax: 416-813-5086
Email: pace@sickkids.ca

Research Interests

Research Activities

Since our discovery of the 'hepoxilins', we have shown that these compounds possess a diversity of interesting and potentially important biological activities in the cell. Of special interest has been the finding that the native hepoxilins mobilize calcium from internal stores in human neutrophils and this release of calcium leads to the desensitization of the cell to well known inflammatory mediators. Hepoxilins have recently been identified as PEEC (pathogen elicited epithelial chemoattractant) believed to be responsible for the epithelial inflammation and recruitment of neutrophils associated with inflammatory bowel disease (IBD).

We have also shown that the hepoxilins affect second messenger pathways in the neutrophil. Hepoxilin action is mediated via its own receptor which is localized intracellularly. To date, hepoxilin receptors have been identified in the human neutrophil and in the brain. Hepoxilin action is directly mediated via receptor binding. Calcium changes in the cell induced by hepoxilins may also be involved in the reported actions of hepoxilins in causing the release of insulin from pancreatic beta-cells, and in the potentiation of vasoconstriction by norepinephrine in vascular tissue.

Our major direction has moved into the development of hepoxilin stable analogs as potential therapeutics in disease. We have synthesized a number of stable analogs of the hepoxilins termed PBTs, and have demonstrated that these compounds bind to the hepoxilin receptor, and inhibit calcium release. Additionally, a specific PBT (PBT-1) potently inhibits the pulmonary fibrosis in vivo in mice, and another (PBT-3) is a potent thromboxane receptor antagonist leading to inhibition of platelet aggregation in vitro and to inhibition of thrombosis in vivo.

A water soluble analog, PBT-10, causes a decrease in plasma glucose in vivo in the streptozotocin diabetic rat. Recent findings have demonstrated that the PBTs cause apoptosis in vitro of the human CML leukaemia cell line, K562 and cells from patient peripheral blood without affecting normal cells. The compounds are apoptotic in vivo in an animal model in which solid tumours were generated after cancer cell transplantation. These studies demonstrate that the PBTs can act as a structural framework for the development of novel therapeutics in the above disease states with combined anti-inflammatory, anti-thrombotic and anti-cancer properties.

Future Research Interests

The isolation and characterization of the 'hepoxilin receptor' is ongoing. We are also investigating through receptor/ligand studies whether hepoxilin binding is altered in disease, specifically in diabetes, cardiovascular disease and cancer. Of interest to these studies is our recent chemical synthesis of a new hepoxilin analog which can act as a tool for the isolation of the hepoxilin receptor. Further investigation of the effect of the PBTs in other cancers is in progress.

Publications

Qiao, N., Reynaud, D., Abdelhaleem, M. and Pace-Asciak, CR. Hepoxilin analogs, PBT-3 and PBT-4, cause apoptosis of Gleevec-resistant K562 cells in vitro. IN VIVO, 21: 267-271, 2007.

Cecil R, Pace-Asciak.  The Hepoxilins and their Analogs – a review of their biology. Br. J. Pharmacol 158: 972-981, 2009.

Etienne Pouteau, Olivier Apriklan, Catherine Grenot, Denis Reynaud, Cecil Pace-Asciak, Claude Y. Cuilleron, Euridice Castaneda-Gutierrez, Julie Moulin, Gregory Pescia, Carine Beysen, Scott Turner and Katherine Macé.  A low alpha-linoleic intake during early life increases adiposity in the adult guinea pig.  Nutrition & Metabolism 7: 8, 2010.
Open access viewing at http://www.nutritionandmetabolism.com/content/7/1/8

Pace-Asciak, Cecil, R.  Hepoxilins in Cancer and Inflammation – use of Hepoxilin Antagonists. Cancer Metastasis Reviews, 30: Issue 3-4, 493-506, 2011.

Brahmbhatt Viral, Oliveira Manuel, Briand Muriel, Perrisseau Geneviève, Schmid Viktoria Bastic, Destaillats, Frédéric, Pace-Asciak Cecil, Bosco Nabil, Benyacoub Jalil. Protective Effects of Dietary EPA and DHA on Ischemia-Reperfusion Induced Intestinal Stress. J. Nutr. Biochem. 24: 104-111, 2013.

Cecil R. Pace-Asciak, Xiang Li, Denis Reynaud, Na Qiao, Peter Demin, Mohamed Abdelhaleem. Alterations in eicosanoid levels during U937 bcl-xL tumour growth suppression and recovery in NU/NU mice in vivo—Involvement of phospholipase A2. Prostaglandins and Other Lipid Mediators. 107: 43-47, 2013.

Nabil Bosco, Viral Brahmbhatt, Manuel Oliveira, Francois-Pierre Martin, Pia Lichti, Frederic Raymond, Robert Mansourian, Sylviane Metairon, Cecil Pace-Asciak, Viktoria Bastic Schmid, Serge Rezzi, Dirk Haller and Jalil Benyacoub.  Effect of fish oil intake on intestinal  eicosanoids and inflammation in a mouse model of colitis.  Lipids in Health and Disease, 12: 81- 94, 2013.

Masood A, Yi M, Lau M, Belcastro R, Li J, Kantores C, Pace-Asciak CR, Jankov RP, Tanswell AK.  Cyclooxygenase-2 inhibition partially protects against 60% O2-mediated lung injury in neonatal rats. Pediatr. Pulmonol. 2013, Nov 23. doi:10.1002/ppul.22921. [Epub ahead of print] PubMed PMID: 24273102.