In patients with head and neck cancer undergoing CCRT, the early nutritional management reduces weight loss and improve outcome.

In this review, we discuss the available experimental evidences supporting the chemopreventive efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) on colorectal cancer and the biological basis for their possible role as anticancer agents. Although the comprehension of the mechanisms underlying the effects of these drugs on colon cancer cells is incomplete, research efforts in identifying the biochemical pathway by which NSAIDs exert their chemopreventive effect have provided a rationale for the potential use of NSAIDs alone or in combination with conventional and experimental anticancer agents in the treatment of colorectal cancer. In this paper, we review three main issues: (i) the role of COX-2 in colon cancer; (ii) the common death pathways between NSAIDs and anticancer drugs; and (iii) the biological basis for the combination therapy with COX-2 selective inhibitors and new selective inhibitors of growth factor signal transduction pathways. ROLE OF COX-2 IN COLON CANCERColorectal cancer is the third most common cancer in the world, and the second most common cause of cancer-related death. Despite the development of new strategies of aggressive surgical and adjuvant therapy, little progress has been made in the successful management of advanced disease; therefore, much hope is currently placed on chemoprevention.A large body of evidence from epidemiological studies and clinical trials in patients with the hereditary colon cancer syndrome, familial adenomatous polyposis coli (FAP) indicates that aspirin and related drugs, known as nonsteroidal antiinflammatory drugs (NSAIDs), which share the property of inhibiting the cyclooxygenase (COX) enzyme, hinder the development of colon cancer and perhaps other cancers as well.COX is the rate-limiting enzyme for the synthesis of eicosanoids, such as prostaglandins, from arachidonic acid. Two COX isoforms have been identified: the constitutively expressed COX-1 and the inducible COX-2. COX-1 is a housekeeping gene and has an important role in protecting the gastroduodenal mucosa. The COX-2 gene, an immediate-early response gene, is rapidly induced in response to tumour promoters, cytokines, and growth factors Di Popolo et al, 2000). NSAIDs may achieve different degrees of inhibition of COX-1 and COX-2 and can be grouped into selective and nonselective inhibitors of COX-2.The development of COX-2-specific inhibitors, like celecoxib and rofecoxib, drugs that maintain their anti-inflammatory properties while preserving the biosynthesis of protective prostaglandins, further raised interest in this field. A large body of research was therefore performed to clarify the relative involvement of the two COX isoforms in colorectal carcinogenesis and the role of COX-2-selective inhibitors as chemopreventive agents.COX-2, but not COX-1, expression was found to be increased in colorectal cancer (Eberhart et al, 1994): approximately 50% of adenomas and 80 -85% of adenocarcinomas showed increased expression of COX-2. This observation was later confirmed by other investigators. Mo...

The aim of the present study was to evaluate the expression of the heat shock protein 60 (HSP60), a mitochondrial matrix-associated protein belonging to the chaperonin family, in colorectal adenomas and cancers, comparing them to normal colonic tissues and hyperplastic polyps. We performed both immunohistochemistry and Western blot analysis for HSP60. Immunohistochemistry resulted positive in all tubular adenomas and infiltrating adenocarcinomas. By contrast, normal tissues and hyperplastic polyps were negative. Quantitative analysis showed that tubular adenomas with different levels of dysplasia did not present statistical differences concerning HSP60 positivity. In addition, carcinomas always showed the highest expression. Western blot analysis confirmed these observations. These data suggest that HSP60 over-expression is an early event in carcinogenesis. We suspect that HSP60 plays a different role in colorectal carcinogenesis with respect to that in normal cells, which foresees its possible use as diagnostic and prognostic tools.

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PGE2 plays a critical role in colorectal carcinogenesis. We have previously shown that COX-2 expression and PGE2 synthesis are mediated by IGF-II/IGF-I receptor signaling in the Caco-2 cell line and that the pathway of phosphatidylinositol 3-kinase (PI3K)/Akt protects the cell from apoptosis. In the present study, we demonstrate that PGE2 has the ability to increase Ras and PI3K association and decrease the level of apoptosis in the same experimental system. The effect of PGE2 on PI3K/Ras association is dependent on the activation of EP4 receptor, the increase of cAMP levels, and the activation of PKA. In fact, treatment of cells with the PKA inhibitor H89 decreases the association of Ras and PI3K and Ras-associated PI3K activity. PKA inhibitor H89 is able to decrease threonine phosphorylation of Akt and to increase serine phosphorylation of Akt by p38 MAPK and counteracts the cytoprotective effect induced by PGE2. In addition, PGE2 is able to activate p38 MAPK and the inhibition of p38 MAPK, with SB203580 specific inhibitor or with dominant negative MKK6 kinase, is able to revert the apoptotic effect of H89 and serine phosphorylation of Akt. The effect of PGE2 on Caco-2 cell survival through PKA activation is mediated and regulated by the balance of threonine/serine phosphorylation of Akt by p38 kinase and PI3K. In conclusion, our data elucidate a novel mechanism for regulation of colon cancer cell survival and provide evidences for new combinatory treatments of colon cancer.