Colon cancer chemoprevention: Clinical development of aspirin as a chemopreventive agent

Krishnan, Koyamangalath; Brenner, Dean E.

doi:10.1002/(sici)1097-4644(1997)28/29+<148::aid-jcb18>3.0.co;2-d

Cited by 15 publications

(11 citation statements)

References 40 publications

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“…Several epidemiologic studies have shown that prolonged use of aspirin is associated with a significant reduction in the risk of developing and/or dying from cancer of the colon (1)(2)(3). Other nonsteroidal anti-inflammatory drugs (NSAIDs), have also been reported to cause a reduction in size and number of adenomas in familial adenomatous polyposis patients (4 -6).…”

Section: Introductionmentioning

confidence: 99%

Subepithelial Myofibroblasts Express Cyclooxygenase-2 in Colorectal Tubular Adenomas

Adegboyega

Ololade

Saada

et al. 2004

Clinical Cancer Research

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Purpose: Recent data support the hypothesis that the inducible isoform of cyclooxygenase (COX-2) plays a role in the early stages of colonic carcinogenesis and that nonsteroidal anti-inflammatory drugs (NSAIDs) retard the development of colon cancer by modulating COX-2. However, the cell types responsible for producing COX-2 in colorectal adenomas remain a subject of controversy.Experimental Design: COX-2 expression in normal colonic mucosa (n ‫؍‬ 50), hyperplastic polyps (n ‫؍‬ 43), sporadic adenomas (n ‫؍‬ 67), and invasive colonic adenocarcinoma (n ‫؍‬ 39) was studied in formalin-fixed and paraffinembedded tissue sections from endoscopy biopsy and colonic resection specimens. Immunohistochemistry (avidin-biotin complex technique with double immunolabeling) was used to identify the phenotypes of COX-2-producing cells.Results: In colorectal adenomas, increased expression of COX-2 was detected and localized to ␣ smooth muscle actin (ؔSMA)-positive subepithelial stromal cells (myofibroblasts) in the periluminal region of the lamina propria in 63 (94%) of 67 cases. In contrast, in normal colonic mucosa and in hyperplastic polyps with intact epithelium, COX-2 expression was found only in macrophages and endothelial cells. In areas in which the surface epithelium was ulcerated in normal mucosa as well as hyperplastic or neoplastic polyps, COX-2 expression was increased in granulation tissue (and present in macrophages, endothelium, and myofibroblasts). In invasive carcinoma, COX-2 expression in myofibroblasts was limited to the adenomatous portion of the tumor and was detected in 62% of cases (n ‫؍‬ 39). In addition, focal expression of COX-2 by malignant epithelial cells was observed in 23% of invasive adenocarcinoma. Conclusions:These results show that increased COX-2 expression in sporadic adenoma of the colon is common and is localized specifically to subepithelial intestinal myofibroblasts. These findings further support the hypothesis that myofibroblasts are important target cells for NSAID-mediated chemoprevention of colorectal cancer.

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Section: Introductionmentioning

confidence: 99%

Subepithelial Myofibroblasts Express Cyclooxygenase-2 in Colorectal Tubular Adenomas

Adegboyega

Ololade

Saada

et al. 2004

Clinical Cancer Research

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“…have shown promise in the prevention of colon cancer are aspirin and related nonsteroidal antiinflammatory drugs (NSAIDs) (2)(3)(4)(5)(6). .…”

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confidence: 99%

“…NSAIDs have inhibited the growth of colorectal cancer cells in vitro (7)(8)(9)(10)(11) , inhibited tumor formation in the colons of carcinogen treated rodents (12)(13)(14), and reduced adenoma counts in humans with familial adenomatous polyposis (15)(16)(17)(18). The most compelling evidence that NSAIDs prevent colon cancer comes from epidemiological data indicating that people who regularly take NSAIDs have a 40-50% reduced risk of dying from this disease compared with matched controls (2,17,19). However, the detrimental side effects of NSAIDs limit their potential as chemopreventative agents (20).…”

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confidence: 99%

Aspirin‐induced activation of the NF‐κB signaling pathway: a novel mechanism for aspirin‐mediated apoptosis in colon cancer cells

et al. 2001

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The aim of this study was to determine whether aspirin mediates an anti-tumor effect by modulation of NF-B signaling. PRINCIPAL FINDINGS Aspirin induces cell death by an active apoptotic processA dose-dependent reduction in cell viability was observed in SW480 colorectal cancer cells treated with aspirin in the dose range 0 -10 mM for 24 h or 0 -2 mM aspirin for 48 h. These doses are comparable to salicylate levels we measured in serum (0.05-1.13 mM) from human subjects given a short analgesic dose (600 mg qid) of aspirin. The reduction in cell viability was accompanied by an increase in cell death due to apoptosis, as determined by quantitation of cells showing phosphatidylserine externalization and cell morphology. Treatment in the presence of cycloheximide showed that aspirin-induced (10 mM) cell by death required de novo protein synthesis, confirming that death occurred through an active process, not passive necrosis. Aspirin induces apoptosis in association with degradation of IB␣ and nuclear translocation of NF-BNext, we examined the involvement of the NF-B signaling pathway in the apoptotic response of SW480 cells to aspirin. Experiments were performed in the absence of tumor necrosis factor (TNF) or other stimulating cytokines, as it is under these experimental conditions that aspirin induced apoptosis. We found that prolonged treatment with aspirin (0.5-2 mM for 48 h or 3-20 mM for 24 h) induced a dose-dependent reduction in cytoplasmic IB␣ levels that correlated with the reduction in the number of viable cells. Levels of control protein (Cu/ZnSOD) were unaffected by aspirin. Mutation of IB␣ at the critical S32/36 phosphorylation sites (IB S32/36 -tag) and preincubation of cells with the MG132 proteasome inhibitor blocked aspirin-induced reduction in IB␣ levels. These results indicate that aspirin mediates phosphorylation and subsequent proteosome-mediated degradation of IB␣ and suggest that this degradation is associated with aspirin-induced cell death.Electrophoretic mobility shift assays (EMSAs) revealed that aspirin-induced IB␣ degradation was accompanied by a dose-dependent specific increase in nuclear NF-B (p50/p65) DNA binding complexes (Fig. 1A, B). The findings from EMSAs were further corroborated by immunocytochemistry. Before aspirin treatment, p65 was localized mainly in the cytoplasm, but after 24 h treatment with 10 mM aspirin, there was extensive nuclear staining for the protein (Fig. 1D). These results establish that 24 h exposure to aspirin activates the NF-B pathway colorectal cancer cells. Aspirin-induced IB␣ degradation and NF-B nuclear translocation precede cell deathTo investigate the possibility that NF-B nuclear translocation was a consequence of cell death, we studied the kinetics of the aspirin effects on NF-B signaling and apoptosis. Aspirin (10 mM) treatment induced complete degradation of IB␣ after 2-5 h. Similarly, an increase in nuclear NF-B DNA binding was observed 2 h after treatment and persisted for Ͼ 16 h. In comparison, aspirin-induced apoptosis, determined by externa...

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“…2) Thus, interference with cell proliferation might prevent metastasis formation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin (ASP) and indomethacin (IM) are well-known as potential chemopreventive agents through their modulation of levels of prostaglandins, PGE2 and PGF2α, and cyclooxygenase (COX) in the colon, [3][4][5] and also other organs. [6][7][8][9] In order to evaluate the anti-metastatic potential of NSAIDs, two typical examples, ASP and IM were examined here using our in vivo lung metastasis model.…”

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confidence: 99%

Suppression of Lung Metastasis by Aspirin but Not Indomethacin in an in vivo Model of Chemically Induced Hepatocellular Carcinoma

Futakuchi

Ogawa

Sano³

et al. 2002

Japanese Journal of Cancer Research

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To examine the effect of non-steroidal anti-inflammatory drugs on metastasis formation, aspirin (ASP, 0.5% in diet) and indomethacin (IM, 0.005% in drinking water) were applied to an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. Multiplicity of HCC in the liver increased during ASP or IM treatment without any significant histological alteration. Although absent in the rats killed at the end of the period of carcinogen exposure, lung metastasis at the end of the experiment was found in 100%, 89% and 100% of rats in the control, ASP and IM groups, respectively. Degree of metastasis was classified into three groups according to the number of metastatic nodules, i.e., slight (1-5 nodules), moderate (6-50) and severe (more than 51), which amounted to 0%, 43% and 57% in the control group. ASP significantly reduced the degree of metastasis, the incidences being 33%, 44%, and 11%, respectively, whereas IM was without significant influence. Both agents suppressed cell proliferation in HCCs, without any alteration of pan-cadherin expression. However, expression in HCC of mRNAs for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, both of which are considered to play key roles in attachment of cancer cells to the endothelium, was significantly suppressed by ASP. Thus, the present study demonstrated that ASP, but not IM, has the potential to inhibit lung metastasis of rat HCC in vivo, possibly via reduced attachment of tumor cells to the vascular endothelium. Moreover, these data indicate this in vivo model for induction of rat highly metastatic HCC to be a useful tool for the assessment of the efficacy of therapeutic treatments to block metastasis formation. Key words: Aspirin -Indomethacin -Lung metastasis -in vivo lung metastasis model -VCAM-1We have recently established an in vivo lung metastasis model in which hepatocellular carcinoma (HCC) induced by sequential treatment with two hepatocarcinogens, diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR), metastasize to the lung very frequently. 1) This model has advantages for investigation of the mechanisms of multistep metastasis of malignant tumors and for the assessment of the efficacy of therapeutic treatments against metastasis in vivo.The metastatic cascade is a continuous process which begins with proliferation of the primary tumor and ends with proliferation of the metastatic foci.2) Thus, interference with cell proliferation might prevent metastasis formation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin (ASP) and indomethacin (IM) are wellknown as potential chemopreventive agents through their modulation of levels of prostaglandins, PGE2 and PGF2α, and cyclooxygenase (COX) in the colon, [3][4][5] and also other organs. [6][7][8][9] In order to evaluate the anti-metastatic ...

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Colon cancer chemoprevention: Clinical development of aspirin as a chemopreventive agent

Cited by 15 publications

References 40 publications

Subepithelial Myofibroblasts Express Cyclooxygenase-2 in Colorectal Tubular Adenomas

Subepithelial Myofibroblasts Express Cyclooxygenase-2 in Colorectal Tubular Adenomas

Aspirin‐induced activation of the NF‐κB signaling pathway: a novel mechanism for aspirin‐mediated apoptosis in colon cancer cells

Suppression of Lung Metastasis by Aspirin but Not Indomethacin in an in vivo Model of Chemically Induced Hepatocellular Carcinoma

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