thromboxane-a2 and Colonic-Neoplasms

This report reviews the author's involvement in the growth of ideas and basic concepts in myocardial ischemia resulting in the histological changes of myocardial infarction. Concepts arising from the study of myocardial substrate utilization, activation of the inducible form of nitric oxide synthase and production of prostacyclin and thromboxane in the infarcted heart are presented. New approaches are discussed dealing with the effects of nonsteroidal anti-inflammatory drugs on myocardial production of nitric oxide and prostanoids, and with the relevance of the inducible form of cyclooxygenase. The review also records a number of significant similarities between angiogenesis in the ischemic heart and some cancers. Angiogenesis in both instances originates from inflammatory reactions, illustrating how different tissues and organs such as ischemic heart muscle and cancer react to similar pathological stimuli in an identical manner. This multifocal approach opens new concepts on myocardial ischemia and cancer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colonic Neoplasms; Cyclooxygenase Inhibitors; Endothelial Growth Factors; Epoprostenol; Gene Transfer Techniques; Genetic Therapy; Humans; Lymphokines; Myocardial Infarction; Myocardial Ischemia; Myocardium; Neovascularization, Pathologic; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The actions of prostanoids in various physiological and pathophysiological conditions have been being examined using mice lacking different prostanoid receptors. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic agent. PGF2alpha was found to be an essential inducer of labor. Several important actions of PGE2 are exerted via each of the four PGE2 receptor subtypes: EP1, EP2, EP3 and EP4. PGE2 participated in colon carcinogenesis via the EP1. PGE2 also participates in ovulation and fertilization and contributes to the control of blood pressure under high-salt intake via the EP2. PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3. It regulated the closure of ductus arteriosus and showed bone resorbing action via the EP4. PGD2 was found to be a mediator of allergic asthma. These studies have revealed important roles of prostanoids, some of which had not previously been known.

Topics: Animals; Asthma; Bicarbonates; Colonic Neoplasms; Dinoprost; Dinoprostone; Female; Fever; Hypertension; Inflammation; Labor, Obstetric; Mice; Mice, Knockout; Pregnancy; Prostaglandins; Receptors, Prostaglandin; Reproduction; Thrombosis; Thromboxane A2

Thromboxane A2 (TXA2) is known to stimulate colonic cancer cell proliferation, although the mechanism has not been clarified. In this study, we compared the expression levels of Kv7.1 K(+) channels between human colorectal cancer tissue and the accompanying non-tumor mucosa. Kv7.1 proteins were found to be consistently up-regulated in the cancer tissues from different patients. Kv7.1 was also expressed in human colonic cancer cell lines. Treatment of colonic cancer cells with 9,11-epithio-11,12-methano-thromboxane A2 (STA2), a stable analogue of TXA2, significantly increased whole-cell K(+) currents sensitive to chromanol 293B, an inhibitor of Kv7.1 channels, in parallel with an increased expression of Kv7.1 proteins. In contrast, TXB2, an inactive metabolite of TXA2, had no effects on expression level and function of Kv7.1. A TXA2 receptor antagonist (SQ29548) and an inhibitor of cAMP-dependent protein kinase (Rp-8-Br-MB-cAMPS) inhibited STA2-induced increases in both Kv7.1 expression and chromanol 293B-sensitive K(+) currents. Interestingly, STA2-stimulated proliferation of colonic cancer cells was inhibited by chromanol 293B. These results suggest that Kv7.1 channels are involved in the TXA2-induced cancer cell proliferation and that they are up-regulated by the TXA2 receptor-mediated cAMP pathway.

Topics: Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Intestinal Mucosa; KCNQ1 Potassium Channel; Protein Kinase Inhibitors; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxane B2; Up-Regulation

In the present study, the effect of normal (5% by wt) and high (23.5% by wt) corn oil diets on prostanoid production and on the lipid composition of preneoplastic colonic epithelium was investigated. CF1 mice (female, 3-4-weeks-old) were fed a normal corn oil diet ad libitum and were treated with the colon carcinogen 1,2-dimethylhydrazine (DMH, 20 mg/kg/wk) or saline (control) for 24 wk. At this stage, all animals received the AIN-76 diet (normal corn oil) ad libitum. Following the last injection, half of the animals from each treatment group were randomly allocated to a high corn oil diet for 5 to 10 wk, whereas the remaining animals continued on the normal corn oil diet. After 5 wk of feeding, the colonic mucosa of carcinogen-treated animals had a higher level of bicyclic prostaglandin E2 (PGE2) than had the animals in the control groups; prostanoid synthesis in the colonic mucosa of control animals was unaffected by the high corn oil diet. Preneoplastic colonic mucosa of animals fed the high corn oil diet had a significantly higher level of PGE2 than corresponding control colonic mucosa. The 6-keto-prostaglandin F1 alpha/thromboxane B2 ratio was significantly lower in the DMH-treated groups than in the control groups, and was unaffected by dietary treatments. After 10 wk of feeding a particular diet, the differences in the fatty acid composition between the control and DMH-treated groups were minor. Our findings demonstrate that the preneoplastic colonic epithelium differs from that of normal epithelium with respect to prostanoid synthesis.

Topics: 1,2-Dimethylhydrazine; Animals; Colonic Neoplasms; Corn Oil; Dimethylhydrazines; Dinoprostone; Epoprostenol; Female; Intestinal Mucosa; Lipid Metabolism; Lipids; Mice; Mice, Inbred Strains; Precancerous Conditions; Prostaglandins; Thromboxane A2

Eicosanoids may participate in colon carcinogenesis, as evidenced from work in animal tumor models showing prevention of colon cancer by inhibitors of their synthesis and epidemiologic studies demonstrating reduced risk of colon cancer in long-term users of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). The levels of prostaglandin E2 (PGE2), PGF2 alpha, PGI2, thromboxane A2 (TXA2), and leukotriene B4 (LTB4), which represent the cyclooxygenase and 5-lipoxygenase pathways, were determined in 21 pairs of surgically excised human colon cancer and histologically normal mucosa samples 5 to 10 cm away from the tumor. The levels of PGE2 were elevated in colon cancer samples as compared with histologically normal mucosa samples distant from the cancer (p < 0.01), whereas levels of prostacyclin (PGI2) were decreased (p < 0.05). The differences in the levels of PGF2 alpha, TXA2, and LTB4 between normal and malignant tissue were not statistically significant. No statistically significant association was found between the level of each of the eicosanoids assayed and Dukes' stage of colon cancer. These findings, confirming and extending earlier work from tumors and cell culture, suggest that the protective effect of aspirin and other NSAIDs in the development of human colon cancer may be mediated, at least in part, through their inhibition of arachidonic acid metabolism by cyclooxygenase.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Aspirin; Colonic Neoplasms; Dinoprostone; Eicosanoids; Epoprostenol; Female; Humans; Intestinal Mucosa; Leukotriene B4; Male; Middle Aged; Thromboxane A2; Time Factors