Carcinogenesis
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Although the pharmacological role of beta-carotene in the prevention and treatment of colon cancer has received increasing attention, little is known about the molecular mechanisms of action of this carotenoid. The present study demonstrates that beta-carotene, a natural pigment widely present in fruit and vegetables, inhibits the growth of several human colon adenocarcinoma cell lines (COLO 320 HSR, LS-174, HT-29 and WiDr) by inducing cell cycle arrest in G(2)/M phase and apoptosis. These effects were dose and time dependent and strictly related to cell ability to accumulate the carotenoid. ⋯ On the other hand, no changes in expression of the apoptosis promoter protein Bax were detected. This study represents a novel aspect of the biological profile of beta-carotene and a new step in elucidating the underlying molecular mechanisms of its antitumor action. In addition, since cell growth inhibitory effects were reached at beta-carotene concentrations achievable in vivo following its supplementation, this study provides a rational approach for the use of beta-carotene in colon cancer.
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Components of the pRb/p16/cyclin D1/CDK4 pathway are frequent targets in numerous tumour types, including those of pituitary origin. However, previous studies of pituitary tumours have examined individual components of this pathway. Therefore, to determine their overall contribution we have simultaneously examined the immunohistochemical status of pRb, p16 and cyclin D1 and analysed the CDK4 gene for a characterized activating mutation. ⋯ Cyclin D1 overexpression was observed in 22 of 45 (49%) tumours, however, there was no significant association between overexpression of cyclin D1 and the expression status of either pRb or p16. In addition, no activating mutations within codon 24 of the CDK4 gene were detected. This study provides evidence for the first time that components of the pRb/p16/cyclin D1/CDK4 pathway, either alone or in combination, are frequently deregulated in human pituitary tumours, suggesting that this pathway may be a useful target in drug or gene therapeutic approaches.
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Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumor cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulindac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC58560 on tumor cell growth in relation to COX-2 expression and prostaglandin production. ⋯ In summary, our data indicate that both COX-dependent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicating that the therapeutic effect of NSAIDs cannot be explained by a direct effect of NSAIDs on the epithelial cells alone. For therapeutic purposes, compounds using different targets could be used to minimize side effects while optimizing therapeutic effect.
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Epidemiological, clinical, animal and laboratory studies have all provided evidence for the protective effects of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, against colorectal cancer. The main established target for NSAID action is cyclooxygenase (COX) and the inducible isoform, COX-2, is up-regulated in colorectal cancer. Rat intestinal epithelial cells transfected with a COX-2 expression vector have previously been found to be resistant to butyrate-induced apoptosis. ⋯ In addition, we report that butyrate treatment of carcinoma (HT29) and adenoma (PC/AA/C1) cells leads to up-regulation of COX-2 protein. Thus NS-398 only appears to sensitize human colorectal carcinoma cells expressing COX-2 protein to the growth inhibitory effect of butyrate. As COX-2 is up-regulated in colorectal carcinogenesis, this could have important implications for the selective inhibition of cells expressing COX-2 protein over those lacking COX-2 protein expression and for dietary modification to be considered alongside NSAIDs in the prevention, and possibly treatment, of colorectal cancer.
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We have genotyped 657 Norwegian men, including 282 lung cancer patients (147 non-operable and 135 operable) and 375 healthy referents (210 smokers and 165 non-smokers), to study the possibility that glutathione S-transferase M1 (GSTM1)-null and/or N-acetyl transferase 2 (NAT2)-slow genotypes confer susceptibility towards lung cancer in smokers. Compared with smoking referents, there was a significant over-representation of the GSTM1-null genotype among patients with squamous cell carcinoma (SQ) [odds ratio (OR) = 1.7, 95% confidence interval (95%CI) = 1.1-2.7], and the NAT2-slow genotype among patients with large cell carcinoma or mixed histological diagnosis (LM) (OR = 2.5, 95%CI = 1.0-6.1). In contrast to operable patients, non-operable patients showed a clear over-representation of slow genotypes if they were younger (