Measurement of arachidonate and its metabolites extracted from human normal and malignant gastrointestinal tissues.

Bennett, A. B.; Civier, A.; Hensby, C.N.; Melhuish, P B; Stamford, I F

doi:10.1136/gut.28.3.315

Cited by 93 publications

(39 citation statements)

References 13 publications

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“…It is metabolized both by the COX pathway, which produces PGs, thromboxane and prostacyclin, and by the LOX pathway, which leads to the formation of leukotrienes and lipoxins. Arachidonic acid products synthesized via both pathways could modulate colon carcinogenesis, 45 and some inhibitors, 46 including LOX inhibitors of the arachidonic acid cascade, possess chemopreventive activity in colon carcinogenesis. 47 In this context, the inhibition of PG biosynthesis, 7 LOX 6 and COX-2 48 after silymarin dosing is of interest and important when considering possible mechanisms behind the chemopreventive effect of silymarin found in the present study.…”

Section: Discussionmentioning

confidence: 99%

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Kohno

Tanaka

Kawabata

et al. 2002

Intl Journal of Cancer

135

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The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced colon carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced colonic ACF, being putative precursor lesions for colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced colon carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. ␤-Glucuronidase activity, PGE 2 level and polyamine content were decreased in colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human colon cancer. Colorectal cancer is the third most common malignant neoplasm in the world. 1 In Japan, its incidence has been increasing, and it is now the third leading cause of cancer death. In this context, primary prevention, including chemoprevention, is important.Silymarin, the collective name for an extract from milk thistle [Silybum marianum (L.) Gaertneri], 2 is a naturally occurring polyphenolic flavonoid antioxidant. 3 It is composed mainly (-80%, w/w) of silybin (also called silybinin, silibin or silibinin), with smaller amounts of other stereoisomers, such as isosilybin, dihydrosilybin, silydianin and silychristin. 4 Silymarin protects experimental animals against the hepatotoxin ␣-amanitin 2 and has a strong antioxidant property. 5 Other biologic properties of silymarin and its components have been reported, including inhibition of LOX 6 and PG synthetase. 7 For over 20 years, silymarin has been used clinically in Europe for the treatment of alcoholic liver disease and as an antihepatotoxic agent. 8 As a therapeutic agent, it is well tolerated and largely free of adverse effects. 5 It might be a potent antica...

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Section: Discussionmentioning

confidence: 99%

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Kohno

Tanaka

Kawabata

et al. 2002

Intl Journal of Cancer

135

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“…Deregulation of the prostanoid synthesis plays an important role in pathogenesis and cancer progression (Surette et al, 1999). Prostanoid synthesis in neoplasms of breast, lung, colon, and also in neuroepithelial tumors of the central nervous system exceeds the levels of normal tissues (Bennett et al, 1977(Bennett et al, , 1987Castelli et al, 1989). The initial step in the biochemical pathway of prostanoid synthesis is the release of arachidonic acid from cellular membranes mediated by phospholipase A 2 .…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

et al. 2003

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Cancer formation and progression is a complex process determined by several mechanisms that promote cell growth, invasiveness, neo-angiogenesis, and render neoplastic cells resistant to apoptosis. The tumor suppressor p53 and the proto-oncogenic factor ets-1 are important regulators of such mechanisms. While it is well established that p53 and ets-1 influence various aspects of cell behavior by regulating the transcription of specific genes, little is known about the functional relationship between these transcription factors. We found that the gene encoding thromboxane synthase (TXSA), which we recently identified as a factor promoting invasion and resistance to apoptosis in gliomas, is a novel target gene for both p53 and ets-1. We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and interrelated manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. Negative interference with ets-1 transcription requires functional p53 and is lost in mutant p53 proteins. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53. An important implication of our findings is that the loss of p53-mediated negative control over ets-1-dependent transcription may lead to the acquisition of an invasive phenotype in tumor cells.

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“…Overexpression of COX-2 inhibits apoptosis and increases the invasiveness of malignant cells (15,16). Amounts of COX-2 are increased in transformed cells and tumors (7,(17)(18)(19), which results in enhanced synthesis of prostaglandins in malignant tissue (20,21). Given these data, a reasonable strategy for inhibiting carcinogenesis is to suppress the expression of COX-2 (22,23).…”

mentioning

confidence: 99%

Dihydroxy Bile Acids Activate the Transcription of Cyclooxygenase-2

Zhang¹,

Subbaramaiah²,

Altorki³

et al. 1998

Journal of Biological Chemistry

188

125

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Measurement of arachidonate and its metabolites extracted from human normal and malignant gastrointestinal tissues.

Cited by 93 publications

References 13 publications

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane‐induced colon carcinogenesis in male F344 rats

Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

Dihydroxy Bile Acids Activate the Transcription of Cyclooxygenase-2

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