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2.
Br J Cancer ; 101(3): 483-91, 2009 Aug 04.
Article in English | MEDLINE | ID: mdl-19638987

ABSTRACT

BACKGROUND: Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways. METHODS: Microarray experiments identified genes regulated by COX-2 in HCA7 CRC cells. In vitro and in vivo regulation of DRAK2 (DAP kinase-related apoptosis-inducing kinase 2 or STK17beta, an apoptosis-inducing kinase) by COX-2 was validated by qRT-PCR. RESULTS: Inhibition of COX-2 induced apoptosis and enhanced DRAK2 expression in HCA7 cells (4.4-fold increase at 4 h by qRT-PCR, P=0.001), an effect prevented by co-administration of PGE(2). DRAK2 levels were suppressed in a panel of human colorectal tumours (n=10) compared to normal mucosa, and showed inverse correlation with COX-2 expression (R=-0.68, R2=0.46, P=0.03). Administration of the selective COX-2 inhibitor rofecoxib to patients with CRC (n=5) induced DRAK2 expression in tumours (2.5-fold increase, P=0.01). In vitro silencing of DRAK2 by RNAi enhanced CRC cell survival following COX-2 inhibitor treatment. CONCLUSION: DRAK2 is a serine-threonine kinase implicated in the regulation of apoptosis and is negatively regulated by COX-2 in vitro and in vivo, suggesting a novel mechanism for the effect of COX-2 on cancer cell survival.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis , Colorectal Neoplasms/pathology , Cyclooxygenase 2/physiology , Protein Serine-Threonine Kinases/genetics , Apoptosis Regulatory Proteins/antagonists & inhibitors , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Dinoprostone/physiology , Gene Expression Regulation, Neoplastic , Humans , Oligonucleotide Array Sequence Analysis , Protein Serine-Threonine Kinases/antagonists & inhibitors , RNA Interference
3.
Ir J Med Sci ; 178(2): 201-8, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19340516

ABSTRACT

BACKGROUND: Cyclo-oxygenase-2 (COX-2) is up-regulated in malignant tumours rendering it an attractive target for cancer therapeutics. However, whether long-term antagonism maintains its initial efficacy on established tumours is unclear. METHODS: 4T1 cells were injected into the mammary fat pad of BALB/c mice (n = 8). Once tumour deposits were established, animals were randomized into two equal groups to receive either a selective COX-2 inhibitor (SC-236) or a drug vehicle. Further animals similarly treated (n = 7) were studied in diuresis cages allowing urine capture and analysis by mass spectrometry to determine Prostaglandin F-1 levels (PGF-1). In addition, both wild-type receiving SC-236 and COX-2 knockout mice receiving either SC 236 or vehicle were subjected to the same studies to determine whether tumour-derived or host-derived (stromal) COX-2 was the critical element. Finally, BALB/c mice with 4T1 tumours (n = 7) were treated with a combination of COX-2 and lipoxygenase (LOX) inhibition to attenuate this escape phenomenon. RESULTS: While selective COX-2 inhibition initially retarded tumour growth, a rapid increase in tumour growth rate occurred later (day 9). This escape phenomenon correlated with an increase in urinary PGF-1 levels. An identical trend was also observed whether COX-2 knockout mice received SC-236 or not, suggesting that this effect is due to increased tumour-derived COX-2 production rather than recovery of host COX-2 functional capacity. Finally, dual inhibition of COX and LOX pathways attenuated this escape process. CONCLUSION: The anti-neoplastic effects of selective COX-2 inhibition may not be sustained as tumours demonstrate an escape capacity. However, this phenomenon maybe attenuated by a combination of COX/LOX inhibitors.


Subject(s)
Breast Neoplasms/enzymology , Cyclooxygenase 2 Inhibitors/therapeutic use , Cyclooxygenase 2/metabolism , Lipoxygenase/metabolism , Animals , Cyclooxygenase 2/drug effects , Disease Progression , Female , Lipoxygenase/drug effects , Mice , Mice, Inbred BALB C , Models, Animal , Random Allocation
4.
J Thorac Cardiovasc Surg ; 132(1): 72-9, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16798305

ABSTRACT

OBJECTIVES: Omega-3 fatty acids exhibit anti-inflammatory, antithrombotic, and antiarrhythmic properties. We investigated the extent and underlying mechanism of protection conferred by a pre-emptive omega-3 infusion in a model of regional cardiac ischemia-reperfusion injury. METHODS: New-Zealand White rabbits received either the omega-3 infusion or a control infusion of 0.9% saline (n = 14 in each group). The large marginal branch of the left coronary artery was occluded for 30 minutes, cardiac function was assessed during 3 hours of reperfusion, and infarct size was measured. Pretreatment-induced alterations in myocardial membrane fatty acid composition and intramyocardial heat shock protein 72 were additionally assessed (n = 5 in each group). Serum markers of myocardial membrane oxidative stress, malonaldehyde and 8-isoprostane, were also determined. Results are expressed as means +/- standard error of the mean and significance was tested with analysis of variance. RESULTS: Pretreatment increased myocardial membrane omega-3 fatty acid content 5-fold, from 0.94% +/- 0.07% in controls to 5.38% +/- 0.44% in the omega-3 group (P < .01), and it produced a 225% elevation of levels of heat shock protein 72 (P = .019) before ischemia-reperfusion. This was associated with a 40% reduction in infarct size (P < .01). Whereas the reperfusion-induced rise in malonaldehyde levels was higher with omega-3 pretreatment, 10.2 +/-1.5 micromol/L versus 6.1 +/- 0.7 micromol/L in controls (P = .04), 8-isoprostanes showed a 9-fold reduction, 679 +/- 190 pg/mL in controls vs 74 +/- 45 pg/mL in the omega-3 group (P = .0077). CONCLUSIONS: A pre-emptive omega-3 infusion significantly reduces infarct size through the dual mechanisms of upregulation of heat shock protein 72, a key preconditioning protein, and a dramatic increase in the omega-3 content of myocardial membranes, which appears to facilitate a shift in oxidant ischemia-reperfusion injury. Further study to optimally shorten the pretreatment regimen for this potentially acceptable infusion will now be pursued.


Subject(s)
Fatty Acids, Omega-3/pharmacology , Ischemic Preconditioning, Myocardial/methods , Myocardial Reperfusion Injury/prevention & control , Animals , Arachidonic Acid/analysis , Blotting, Western , Cell Membrane/chemistry , Dinoprost/analogs & derivatives , Dinoprost/metabolism , Disease Models, Animal , Docosahexaenoic Acids/analysis , Eicosapentaenoic Acid , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/metabolism , Fatty Acids, Unsaturated/analysis , HSP72 Heat-Shock Proteins/analysis , HSP72 Heat-Shock Proteins/metabolism , Immunohistochemistry , Infusions, Intravenous , Male , Malondialdehyde/analysis , Myocardial Reperfusion Injury/physiopathology , Myocardium/chemistry , Oxidation-Reduction , Oxidative Stress , Rabbits , Up-Regulation , Ventricular Function, Left
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