Cyclooxygenase 2 inhibition in patients with non–small cell lung cancer: Is this still a valid target for therapy?

Abstract

The link between chronic inflammation and cancer is well recognized and was first proposed by Virchow in 1863. 1 He observed leukocytes at tumor sites and suggested that this "lymphoreticular" infiltrate at sites of chronic inflammation was connected to the development of cancers. The link between inflammatory bowel disease and colon cancer and chronic hepatitis and hepatocellular carcinoma as well as chronic gastritis induced by Helicobacter pylori infection and gastric cancer are well recognized observations that support this proposal. 1 It has also been proposed that lung cancer in smokers is linked to the chronic inflammation induced by reactive oxygen species in the cigarette smoke. 2 Chronic inflammatory states are characterized by repeated tissue injury followed by attempts at tissue repair. This cycle of repeated injury and repair can promote features of carcinogenesis such as DNA damage, cellular proliferation, and cell survival.The role of inflammation in the development of cancer was further supported by epidemiologic studies that suggested a reduced incidence of several cancers in individuals taking aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) regularly. 3 NSAIDs exert their antiinflammatory effects primarily by inhibiting the cyclooxygenase enzyme (COX). COX exists in 2 isoforms: COX-1 and COX-2. 4 COX-1 has constitutive activity in nearly all cells and is involved in several homeostatic functions such as maintaining gastric mucosal integrity and resisting the activity of gastric acid, normal renal tubular function, and platelet function. COX-2 is the inducible form of the enzyme, and is not expressed in the majority of normal tissues but is upregulated in inflammatory tissues and many cancers in response to cytokines, growth factors, and hormones. COX-2-derived prostaglandin E2 (PGE2) is the primary mediator of inflammation and appears to have tumor-promoting properties, including tumor invasion, resistance to apoptosis, angiogenesis, and suppression of host immunity. [5][6][7] Preclinical studies have suggested that inhibition of COX-2 can result in a reduction in tumor growth in several cancers, including non-small cell lung cancer (NSCLC). [8][9][10] With the introduction of selective COX-2 inhibitors, there was an expectation that the inducible isoform of the COX enzyme can be targeted for both antiinflammatory and potentially anticancer properties while sparing the protective effects of the COX-1 isoform. COX-2 inhibitors were therefore evaluated for both cancer prevention and anticancer therapy. Celecoxib, a COX-2 inhibitor, was evaluated in patients with familial adenomatous polyposis, a genetic condition resulting from mutations in the adenomatous polyposis coli (APC) gene that leads to multiple adenomatous polyps with a nearly 100% risk of colon cancer. Preclinical studies have suggested that despite the presence of a mutation in the APC gene, blocking the activity of COX-2 and the production of PGE2 can prevent development of the adenomatous polyps. These preclinical resu...

Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

“…All class I HDACs and HDAC 6 (a class IIb HDAC) play crucial roles in the survival of the chosen cancer cell lines 2, 4 . While COX-2 is ubiquitously expressed in the MCF-7 18a and A549 30 cell lines, its expression is barely discernible in the HCT-116, 22b a colon cancer cell line that is highly sensitive to HDAC inhibition through COX-2 independent mechanism(s). 22c Prostate cancer cell lines (LNCaP and DU-145) were chosen to evaluate the selectivity of our compounds towards androgen dependent prostate cancer.…”

The natural polyphenol curcumin induces apoptosis by suppressing STAT3 signaling in esophageal squamous cell carcinoma

“…Noteworthily, Cox2, which catalyzes the conversion of arachidonic acid to prostaglandins, is inducible by many cytokines in an STAT3-dependent manner [ 48 , 49 ]. It is highly expressed in many premalignant and malignant lesions, including nasopharyngeal carcinoma, lung cancer, breast cancer [ 50 – 52 ]. A number of studies indicated that Cox2 plays an important role in apoptosis, angiogenesis and tumor invasion [ 53 ].…”