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

Li X, Qiao N, Reynaud D, Abdelhaleem M, Pace-Asciak CR. The Hepoxilin analog, PBT-3, inhibits the growth of K-562 CML solid tumours in vivo in nude mice. IN VIVO 19 185-190, 2005.

Qiao N, Lam J, Reynaud D, Abdelhaleem M, Pace-Asciak CR. The hepoxilin analog, PBT-3, induces apoptosis in BCR-ABL-positive K562 cells. J. Anti-Cancer Res., 23: 3617-3622, 2003.

Qiao N, Reynaud D, Demin P, Halushka P, Pace-Asciak CR. The thromboxane receptor antagonist PBT-3, a hepoxilin stable analog, selectively antagonizes the TPα isoform in transfected COS-7 cells. JPET, 307: 1142-1147, 2003.

Reynaud D, Clark D, Qiao N, Rand ML, Pace-Asciak CR. The hepoxilin analogue, PBT-3, inhibits primary, platelet-related hemostasis in whole blood measured in vitro with the PFA-100. Thromb. Res. 112: 245-248, 2003.

Reynaud D, Hinek A, Pace-Asciak CR. The hepoxilin analog, PBT-3, inhibits heparin-activated platelet aggregation evoked by ADP. FEBS Lett., 515:58-60, 2002.

Pace-Asciak CR, Reynaud D, Demin P, Aslam R, Sun A. A new family of thromboxane receptor antagonists with secondary thromboxane synthase inhibition. JPET, 301L 618-624, 2002.

Jankov RP, Luo XP, Demin P, Aslam R, Hannan V, Tanswell AK, Pace-Asciak CR. Hepoxilin analogs inhibit bleomycin-induced pulmonary fibrosis in the mouse. JPET, 301: 435-440, 2002.

Reynaud D, Sun A, Demin P, Pace-Asciak CR. Novel platelet anti-aggregating substances. BBRC, 284: 580-582, 2001.

Reynaud D, Sun A, Demin P, Pace-Asciak CR. Improved HPLC method for the combined analysis of phospholipase, lipoxygenase and cyclooxygenase activities in human platelets using acetylated fluorescent anthracene (ADAM) esters. J. Chromatog. B. 762: 175-180, 2001.

Pace-Asciak CR, Reynaud D, Demin P, Nigam S. The hepoxilins. A review. Advances in Experimental Medicine and Biology, 447: 123-132, 1999.

Pace-Asciak CR, Reynaud D, Rounova O, Demin P, Pivnitsky KK. Hepoxilin A3 is metabolized into its omega-hydroxy metabolite by human neutrophils. Advances in Experimental Medicine and Biology, 469: 535-538, 1999.