Cyclooxygenase-2, malondialdehyde and pyrimidopurinone adducts of deoxyguanosine in human colon cells

Casto

2014

WJCO

154

125

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2 (COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following: (1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis; (2) essential features of mammary carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2 (PGE-2) biosynthesis; (3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis; (4) extrahepatic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and (5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer". Key words: Breast Cancer; Cyclooxygenase-2; Nonsteroidal anti-inflammatory drugs; Inflammogenesis; Estrogen; Aromatase Core tip: Mammary carcinogenesis often evolves as a series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of cyclooxygenase-2 (COX-2) and the prostaglandin cascade; reciprocally, agents that block COX-2 have significant value in the chemoprevention and therapy of breast cancer.Harris RE, Casto BC, Harris ZM. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol 2014; 5(4): 677-692 Available from: URL: http://www.wjgnet.com/2218-4333/full/v5/ i4/677.htm DOI: http://dx.doi.org/10.5306/wjco.v5.i4.677 INTRODUCTIONMore than a century ago, Virchow et al [1,2] chronic inflammation leads to cancer development by increasing cellular proliferation [3] . Various models of carcinogenesis have been proposed involving inflammatory stimuli and mediators of wound healing [4][5][6] . The recent discovery of the inducible cyclooxygenase-2 (COX-2) gene has rekindled interest in the causal link between inflammation and cancer, and various models of carcinogenesis have been proposed involving inflammatory stimuli and COX-2 expression [7][8][9][10] . The current review synthesizes and interprets the accumulating body of evidence supporting COX-2 driven inflammogenesis as a ge...

mentioning

confidence: 79%

Cyclooxygenase-2 and the inflammogenesis of breast cancer

Casto

2014

WJCO

154

125

“…Isorhamnetin Tamarixetin * * * * * PGE-2 levels (% of control) Figure 6 Effect of quercetin, rutin quercetin-7-O-sulphate (Q-7-O-SO 4 ), quercetin-3-O-sulphate (Q-3-O-SO 4 ), isorhamnetin and tamarixetin (each 10 mM) on COX-2 enzyme activity, as reflected by PGE-2 levels, in cultures of HCA-7 colon cancer cells. The COX complement of HCA-7 cells is made up almost exclusively of COX-2, while COX-1 is present only to a minor extent (Sharma et al, 2001). Cells were incubated with agents for 6 h, and PGE-2 levels were measured by ELISA.…”

Section: Discussionmentioning

confidence: 99%

“…Human-derived HCA-7 colon cancer cells contain significant levels of COX protein, which has been shown to be almost exclusively COX-2 (Sharma et al, 2001). Therefore, measurement of PGE-2 in the cellular supernatant reflects predominantly COX-2 levels and activity.…”

Section: Effect Of Quercetin Metabolites On Cellular Pge-2 Productionmentioning

confidence: 99%

Characterisation of metabolites of the putative cancer chemopreventive agent quercetin and their effect on cyclo-oxygenase activity

et al. 2004

Quercetin (3,5,7,3 0 ,4 0 -pentahydroxyflavone) is a flavone with putative ability to prevent cancer and cardiovascular diseases. Its metabolism was evaluated in rats and human. Rats received quercetin via the intravenous (i.v.) route and metabolites were isolated from the plasma, urine and bile. Analysis was by high-performance liquid chromatography and confirmation of species identity was achieved by mass spectrometry. Quercetin and isorhamnetin, the 3 0 -O-methyl analogue, were found in both the plasma and urine. In addition, several polar peaks were characterised as sulphated and glucuronidated conjugates of quercetin and isorhamnetin. Extension of the metabolism studies to a cancer patient who had received quercetin as an i.v. bolus showed that (Quercetin removed) isorhamnetin and quercetin 3 0 -O-sulphate were major plasma metabolites. As a catechol, quercetin can potentially be converted to a quinone and subsequently conjugated with glutathione (GSH). Oxidation of quercetin with mushroom tyrosinase in the presence of GSH furnished GSH conjugates of quercetin, two mono-and one bis-substituted conjugates. However, these species were not found in biomatrices in rats treated with quercetin. As cyclo-oxygenase-2 (COX-2) expression is mechanistically linked to carcinogenesis, we examined whether quercetin and its metabolites can inhibit COX-2 in a human colorectal cancer cell line (HCA-7). Isorhamnetin and its 4 0 -isomer tamarixetin were potent inhibitors, reflected in a 90% decrease in prostaglandin E-2 (PGE-2) levels, a marker of COX-2 activity. Quercetin was less effective, with a 50% decline. Quercetin 3-and 7-O-sulphate had no effect on PGE-2. The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites. Naturally occurring flavonoids in the diet are associated with several beneficial health effects and understanding the mechanisms underlying these effects has become the focus of much research. Quercetin (3,5,7,3 0 ,4 0 -pentahydroxyflavone, for structure see Figure 1) is a prime example of such a flavonoid. Its glycosylated form occurs in kale, French beans, broccoli, apples and especially in onions, with an abundance as high as a quarter to half a gram per kg (Hertog et al, 1992). On ingestion with the diet, quercetin glycosides are rapidly hydrolysed to generate quercetin.Epidemiological evidence links diets rich in quercetin with decreased incidence of cardiovascular and neoplastic diseases

“…This may define complementary, indirect chemoprevention targets alongside COX-2. Possible paracrine mediators, in addition to COX-2-derived eicosanoids, include mutagenic COX-2-derived products such as reactive oxygen species and/or malondialdehyde (Sharma et al, 2001). Alternatively, other pro-tumorigenic factors produced by macrophages (Rosenberger et al, 2000;Nau et al, 2002), under the control of COX-2, could mediate the paracrine signal.…”

Section: Discussionmentioning

confidence: 99%

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

Chapple

Hawcroft

et al. 2002

Oncogene

In human colorectal adenomas or polyps, cyclooxygenase-2 is expressed predominantly by stromal (or interstitial) macrophages. Therefore, we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions. We report that macrophages can promote tumorigenic progression of intestinal epithelial cells (evidenced by decreased cellcell contact inhibition, increased proliferation and apoptosis, gain of anchorage-independent growth capability, decreased membranous E-cadherin expression, up-regulation of cyclooxygenase-2 expression, down-regulation of transforming growth factor-b type II receptor expression and resistance to the antiproliferative activity of transforming growth factor-b 1 ) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1 -2 mM) of a selective cyclooxygenase-2 inhibitor had no detectable, direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression. Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer (and other gastro-intestinal epithelial malignancies, which arise on a background of chronic inflammation, such as gastric cancer) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce antineoplastic effects in vitro and in vivo.