Cyclooxygenase-2: a novel target for cancer chemotherapy?

Abstract

Epidemiologic studies have documented a 40-50% reduction in incidence of colorectal cancer in individuals taking nonsteroidal antiinflammatory drugs (NSAIDs). Since NSAIDs are known to inhibit cyclooxygenases (COX-1, COX-2), the basic mechanism of their antitumor effects is conceivably the altered metabolism of arachidonic acid and, subsequently, prostaglandins (PGs). Although COX-2, the inducible isoform, is regularly expressed at low levels in colonic mucosa, its activity increases dramatically following mutation of the APC (adenomatous polyposis coli) gene suggesting that beta-catenin/T-cell factor mediated Wnt-signaling activity may regulate COX-2 gene expression. In addition, hypoxic conditions and sodium butyrate exposure may also contribute to COX-2 gene transcription in human cancers. The development of selective COX-2 inhibitors has made it possible to further evaluate the role of COX-2 activity in colorectal carcinogenesis. To date, at least five mechanisms by which COX-2 contributes to tumorigenesis and the malignant phenotype of tumor cells have been identified, including: (1) inhibition of apoptosis; (2) increased angiogenesis; (3) increased invasiveness; (4) modulation of inflammation/immuno-suppression; and (5) conversion of procarcinogens to carcinogens. A clear positive correlation between COX-2 expression and inhibition of apoptosis has been established, associated with increased PGE2 levels resulting in modulation of pro- and anti-apoptotic factors (e.g., bcl-2, MAKs/ras, caspase-3, Par-4). In terms of angiogenesis and invasiveness, COX-2 activity was found to increase the expression of growth factors (e.g., VDEG, PDGF, bFGF) and matrix metalloproteinases (MMPs). Since COX-2 inhibitors have been demonstrated to interfere with tumorigenesis and apoptosis, COX-2 and its gene product may be attractive targets for therapeutic and chemoprotective strategies in colorectal cancer patients. This may lead to new perspectives that by controlling the cancer phenotype, rather than attempting to eradicate all affected cells, may provide significant benefits to the cancer patient.

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

“…Intact nuclei were collected by cytospin and evaluated for ␤-catenin using fluorescently tagged anti-␤-catenin antibodies mens (34,61,62). Cox-2 contributes to tumorigenesis by inhibiting apoptosis, increasing growth factor expression to promote angiogenesis, and by enhancing matrix metalloproteinase expression to stimulate invasion (63). The membrane-anchored receptor uPAR binds urinary-type plasminogen activator and participates in cell surface-associated plasminogen activation.…”

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

“…COX-2 is highly inducible by the oncogenes ras and scr and other cytokines at the sites of inflammation and cancer (Kam and See, 2000;Turini and DuBois, 2002;Church et al, 2003). Previous studies have shown that most cancer cells are found to exhibit over-expression of COX-2, which can stimulate cellular division and angiogenesis and inhibit apoptosis (Dempke et al, 2001). Accumulated evidence suggests that COX-2 selective inhibitors such as non-steroidal anti-inflammatory drugs (NSAIDS) induce apoptosis by suppressing the COX-2 levels (Huang et al, 2005).…”

Expression of Cyclooxygenase-2 (COX-2) in Colorectal Adenocarcinoma: an Immunohistochemical and Histopathological Study

“…In the last few years there have been many studies on the mechanisms involving the carcinogenesis of colorectal cancer. Inflammatory process and genetics play the key role in neoplasia of colorectal cancer .The identification of an enzyme COX-1 and COX-2, catalyzing fatty oxidation as rate limiting step in the progress from normal cell growth through hyperplasia or to neoplasia has opened up a whole new field of cancer search (Dempke et al, 2001). COX -1 and COX-2 catalyze the first stage in the oxidation of arachidonic acid to prostaglandin (Karahan et al, 2007).…”

“…The majority of the colorectal cancers are derived from adenomas (Wu et al, 2003). It has been hypothesized that the up regulation of COX-2 prolongs the survival of abnormal cells and thereby favors the accumulation of sequential genetic changes, which increases the risk of tumorigenesis (Dempke et al, 2001). However, the over-expression of COX-2 protein in colorectal cancers is likely to occur via several different mechanisms involving complex signaling pathways, since transformed epithelial cells and stromal cells, such as mononuclear cells, fibroblasts, endothelial cells and smooth muscle cells have been shown to express increased levels of COX-2 (Sonoshita et al, 2002).…”

“…COX2 is closely involved in the carcinogenesis process and is over expressed in adenocarcinoma in contrast with non-cancerous mucosal regions in colon cancers and gastric cancers (Tsujii et al, 1998). It is involved in a variety of important cellular functions, including cell growth and differentiation, cancer cell motility and invasion, angiogenesis and immune functions (Dempke et al, 2001). The role of angiogenesis is very important in colorectal cancer and cancercyclooxygenase-2 is a significant angiogenic factor in colorectal cancer tissue (Zhou et al, 2012).…”