Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth

Tutton, P. J. M.; Barkla, D. H.

doi:10.1038/bjc.1980.6

Cited by 71 publications

(13 citation statements)

References 19 publications

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“…Attempts have also been made to assess the influence of PG on colonic epithelial proliferation in vivo. It has been reported that acute parenteral administration of the PG analogs 16,16-dimethyl PGE2 or 16,16-dimethyl-PGF2a failed to alter the proliferative activity of colonic crypt epithelium in normal rats when assessed 4 h after injection of these agents (7). Similarly, the cyclooxygenase inhibitor flubiprofen was without apparent effect on the proliferative activity of colonic crypts, when assessed 4 h after injection of this drug (7).…”

Section: Introductionmentioning

confidence: 98%

“…It has been reported that acute parenteral administration of the PG analogs 16,16-dimethyl PGE2 or 16,16-dimethyl-PGF2a failed to alter the proliferative activity of colonic crypt epithelium in normal rats when assessed 4 h after injection of these agents (7). Similarly, the cyclooxygenase inhibitor flubiprofen was without apparent effect on the proliferative activity of colonic crypts, when assessed 4 h after injection of this drug (7). These negative results are difficult to interpret, since (a) no evidence was provided that the systemic administration of either of the PG analogs or the cyclooxygenase inhibitor altered local colonic PG levels; and (b) proliferative activity was examined only after a brief period of in vivo exposure to the test agents.…”

Section: Introductionmentioning

confidence: 99%

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Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

Craven¹,

Saito²,

DeRubertis³

1983

J. Clin. Invest.

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A B S T R A C T The role of local prostaglandin (PG) synthesis in the modulation of the proliferative activity of colonic epithelium was examined in rat colon. Experimental rats were given either indomethacin (5 mg/kg s.c. every 8 h for three doses) or aspirin (0.5 g/100 g diet for 3 d). In rats treated with indomethacin or aspirin, the incorporation of [3H]thymidine (dThd) into DNA in vivo was increased approximately twofold over control in mucosal scrapings from distal colon, and approximately threefold over control in the proliferating pool of epithelial cells isolated from distal colon.[3H]dThd incorporation into DNA was also examined ex vivo immediately after distal colonic resection. It was approximately twofold higher in mucosa of colonic segments (1-h incubation) from rats treated with indomethacin or aspirin in vivo, compared with corresponding values of segments from control rats. Immunoreactive (i) prostaglandin E (PGE), the dominant PG product of colon segment incubates by high-performance liquid chromatography analysis of [14C]arachidonate metabolites, was markedly (95%) reduced in the media of 1-h colon incubates from indomethacin-or aspirin-treated rats, compared with control rats. Moreover, the cyclic (c)AMP content of mucosa of segments from indomethacin-or aspirintreated rats was significantly lower than that of control rats. Prolonged incubation (4-24 h) of colonic segments from indomethacin-treated rats, in the absence of indomethacin in vitro, led to an eventual return of [3H]dThd incorporation into DNA, iPGE, and mucosal cAMP to control values. Conversely, inclusion of indomethacin (0.25 mM) in the incubations (6 h) of coAddress all correspondence to Dr. Frederick R. DeRubertis.Received for publication 1 April 1983 and in revised form 28 June 1983. lonic segments from indomethacin-treated rats resulted in persistent suppression of iPGE and mucosal cAMP, as well as persistent enhancement of [3H]dThd incorporation into mucosal DNA. However, incubation of colonic segments from control rats (no in vivo drug exposure) with indomethacin or aspirin in vitro for periods up to 24 h failed to alter DNA synthesis, despite marked reduction in media iPGE and lower mucosal cAMP. The latter observations suggested that additional in vivo factors initiated the enhancement of DNA synthesis in indomethacin-or aspirin-treated rats. Exogenous PGE2, D2, I2, or F2a, each of which increased the endogenous mucosal cAMP content of incubated colonic segments from control, indomethacin-or aspirin-treated rats, all suppressed [3H]dThd incorporation into mucosal DNA in vitro. Dibutyryl cAMP, but not dibutyryl cGMP, had an analogous suppressive effect on in vitro [3H]dThd incorporation into DNA. Thus, the present observations are consistent with an inhibitory action of endogenous colonic PG synthesis on the proliferative activity of colonic epithelium. This action may be mediated through cAMP. INTRODUCTIONThe colon is an active site of prostaglandin (PG)' synthesis (1, 2). There is evidence that PG may modulate coloni...

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

Craven¹,

Saito²,

DeRubertis³

1983

J. Clin. Invest.

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“…Some of these properties plausibly make h-escin a prime candidate for a potential cancer chemopreventive agent. For instance, prostaglandin-F 2 a strongly inhibited cell proliferation in dimethylhydrazineinduced rat colon adenocarcinoma (17), and compounds with anti-hyaluronidase activity are associated with an increased resistance to tumors (18). Matsuda et al (19) reported the inhibitory effect of escins isolated from horse chestnut on carrageenan-induced hind paw edema in an animal model for acute inflammation.…”

Section: Introductionmentioning

confidence: 99%

β-Escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21waf1/cip1 in colon cancer cells

Patlolla

Raju

Swamy

et al. 2006

Molecular Cancer Therapeutics

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Extracts of Aesculus hippocastanum (horse chestnut) seed have been used in the treatment of chronic venous insufficiency, edema, and hemorrhoids. Most of the beneficial effects of horse chestnut are attributed to its principal component B-escin or aescin. Recent studies suggest that B-escin may possess anti-inflammatory, antihyaluronidase, and anti-histamine properties. We have evaluated the chemopreventive efficacy of dietary B-escin on azoxymethane-induced colonic aberrant crypt foci (ACF). In addition, we analyzed the cell growth inhibitory effects and the induction of apoptosis in HT-29 human colon cancer cell line. To evaluate the inhibitory properties of B-escin on colonic ACF, 7-week-old male F344 rats were fed experimental diets containing 0%, 0.025%, or 0.05% B-escin. After 1 week, the rats received s.c. injections of azoxymethane (15 mg/kg body weight, once weekly for 2 weeks) or an equal volume of normal saline (vehicle). Rats were continued on respective experimental diets and sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated histopathologically for ACF. Administration of dietary 0.025% and 0.05% B-escin significantly suppressed total colonic ACF formation up to f40% (P < 0.001) and f50% (P < 0.0001), respectively, when compared with control diet group. Importantly, rats fed B-escin showed dose-dependent inhibition (f49% to 65%, P < 0.0001) of foci containing four or more aberrant crypts. To understand the growth inhibitory effects, HT-29 human colon carcinoma cell lines were treated with various concentrations of B-escin and analyzed by flow cytometry for apoptosis and cell cycle progression. B-Escin treatment in HT-29 cells induced growth arrest at the G 1 -S phase, which was associated with the induction of the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 , and this correlated with reduced phosphorylation of retinoblastoma protein. Results also indicate that B-escin inhibited growth of colon cancer cells with either wild-type or mutant p53. This novel feature of B-escin, a triterpene saponin, may be a useful candidate agent for colon cancer chemoprevention and treatment.

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“…A similar tendency to inhibit proliferation has been observed in a rat colon tumour model after treatment with 16,16-dimethyl-PGE 2 . Both in the normal colonic mucosa and in the tumour, a reduction of mitotic index was observed in the highest PG-dose group mediated by an increase of cAMP (Tutton and Barkla, 1980). Prostaglandin E 2 effects in min-mice are mediated by the PG receptors EP2 and 4, which signal via cAMP.…”

Section: Discussionmentioning

confidence: 93%

Prostaglandin E2 stimulates progression-related gene expression in early colorectal adenoma cells

Mauritz¹,

Westermayer²,

Marian³

et al. 2006

Br J Cancer

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Upregulation of cyclooxygenase-2 (COX-2) and prostaglandin-dependent vascularisation in small adenomatous polyps is an essential part of colon carcinogenesis. To study the underlying cellular mechanisms, LT97 and Caco2 human colorectal tumour cells not expressing endogenous COX-2 were exposed to 1 mM prostaglandin E 2 (PGE 2 ) in their medium. At 30 min after addition, expression of c-fos was stimulated 5-fold and 1.3-fold, respectively, depending on the activation of both extracellular signal-regulated kinase and p38. The amount of c-jun in nuclear extracts was increased 20% in LT97 cells. Expression of COX-2 was upregulated 1.7-fold in LT97 cells and 1.5-fold in Caco2 2 h after prostaglandin (PG) addition by a p38-mediated pathway. The known PGE 2 target gene vascular endothelial growth factor (VEGF) was not modulated. Effects of sustained PGE 2 production were studied in VACO235 cells that have high endogenous COX-2 and in LT97 cells infected with an adenovirus expressing COX-2. Prostaglandin E 2 secretion into the medium was 1 -2 nM and 250 pM, respectively. Expression of both VEGF and c-fos was high in VACO235 cells. In LT97 cells, COX-2 upregulated c-fos expression and c-jun content in nuclear extracts 1.7-and 1.2-fold, respectively, in a PG-dependent way. This shows that exogenous PGE 2 as well as COX-2 overexpression affect signalling and gene expression in a way that enhances tumour progression. British Journal of Cancer (2006) Upregulation of cyclooxygenase-2 (COX-2) expression in early adenomas is an essential prerequisite of colorectal carcinogenesis. It causes elevated levels of prostaglandins (PGs) in the tissue and PG-dependent neovascularisation (Eberhart et al, 1994). Adenomatous polyps regress under therapy with non-steroidal anti-inflammatory drugs whose main cellular target is COX-2 (DuBois et al, 1996). Mice carrying a hereditary mutation in the APC gene (min-mice or transgenic DAPC-mice; (de Wind et al, 1998) develop a multitude of intestinal polyps in a COX-2 and prostaglandin E 2 (PGE 2 )-receptor-dependent way (Sonoshita et al, 2001;Seno et al, 2002;Sunayama et al, 2002). Immunohistochemical analysis of tissue sections shows that much of the COX-2 is located in connective tissue but not in the epithelial compartment of the polyps. In the pathology of human colorectal cancer, COX-2 plays a similar role and has become the main target of chemoprevention in high-risk patients (DuBois et al, 1996;Gupta and Dubois, 2001). As in the mouse models, COX-2 is mainly located in the connective tissue of human adenomatous polyps.This raises the question whether PGs produced in the microenvironment (fibroblasts, endothelial cells or macrophages) can in turn affect early premalignant cells and trigger expression of tumour-associated genes. To answer these questions we have established the human colonic adenoma cell line LT97 from microadenomas of a polyposis patient that do not yet express COX-2 or produce PGE 2 (Richter et al, 2001). Tumour-promoting bile acids have been shown to induce expression of ...

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Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth

Cited by 71 publications

References 19 publications

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

β-Escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21waf1/cip1 in colon cancer cells

Prostaglandin E2 stimulates progression-related gene expression in early colorectal adenoma cells

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