Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo.

Cyclooxygenase-2 (COX-2) is expressed within neovascular structures that support many human cancers. Inhibition of COX-2 by celecoxib delays tumor growth and metastasis in xenograft tumor models as well as suppresses basic fibroblast growth factor 2 (FGF-2)-induced neovascularization of the rodent cornea. The present studies were undertaken to evaluate possible mechanisms of the antiangiogenic and anticancer effects of celecoxib. Prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)) were increased in rat corneas implanted with slow-release pellets containing FGF-2 (338.6 ng of PGE(2)/g and 17.53 ng of TXB(2)/g) compared with normal rat corneas (63.1 ng of PGE(2)/g and 2.0 ng of TXB(2)/g). Celecoxib at 30 mg/kg/day p.o. inhibited angiogenesis (78.6%) and prostaglandin production by 78% for PGE(2) (72.65 ng/g) and 68% for TXB(2) (5.55 ng/g). Decreased prostaglandin production in corneas was associated with a 2.5-fold cellular increase in apoptosis and a 65% decrease in proliferation. Similar reductions in proliferation were observed in neovascular stroma (65-70%) of celecoxib-treated (dietary 160 ppm/day) xenograft tumors as well as in tumor cells (50-75%). Apoptosis was also increased in the tumor cells (2.2-3.0-fold) in response to celecoxib. Thus, the antitumor activity of celecoxib may be attributable, at least in part, to a direct effect on host stromal elements, such as the angiogenic vasculature.

Cyclooxygenase-1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites.

1. The maintenance of renal function in decompensated cirrhosis is highly dependent on prostaglandins (PGs). Since PG synthesis is mediated by cyclooxygenase-1 and -2 (COX-1 and COX-2), the present study was designed to examine which COX isoform is involved in this phenomenon. 2. Renal COX-1 and COX-2 protein expression and distribution were analysed by Western blot and immunohistochemistry in nine rats with carbon tetrachloride-induced cirrhosis and ascites and 10 control animals. The effects of placebo and selective COX-1 (SC-560) and COX-2 (celecoxib) inhibitors on urine flow (V), urinary excretion of sodium (U(Na)V) and PGE(2) (U(PGE2)V), glomerular filtration rate (GFR), renal plasma flow (RPF), the diuretic and natriuretic responses to furosemide and renal water metabolism were assessed in 88 rats with cirrhosis and ascites. 3. COX-1 protein levels were found to be unchanged in kidneys from cirrhotic rats. In contrast, these animals showed enhanced renal COX-2 protein expression which was focally increased in the corticomedullary region. Although U(PGE2)V was equally reduced by SC-560 and celecoxib, only SC-560 produced a significant decrease in U(Na)V, GFR and RPF and a pronounced impairment in the diuretic and natriuretic responses to furosemide in rats with cirrhosis and ascites. Neither SC-560 nor celecoxib affected renal water metabolism in cirrhotic rats. 4. These results indicate that despite abundant renal COX-2 protein expression, the maintenance of renal function in cirrhotic rats is mainly dependent on COX-1-derived prostaglandins.

Celecoxib, a selective cyclooxygenase-2 inhibitor, decreases monocyte chemoattractant protein-1 expression and neointimal hyperplasia in the rabbit atherosclerotic balloon injury model.

The inflammation in response to vascular injury is becoming increasingly recognized as a potential contributor to restenosis. Cyclooxygenase-2 (COX-2) is the inducible form of cyclooxygenase and has been shown to be involved in the proinflammatory response of vascular tissue. Bilateral femoral artery lesions were induced by air desiccation in New Zealand White rabbits followed by high cholesterol diet feeding for 28 days. Balloon injury and stent implantation were performed at the preinjured vessel segments. Immunostaining showed that uninjured vessel segments stained positive only for COX-1 but not for COX-2. Injured vessel segments showed, in addition to COX-1, significant positive staining for COX-2. In the efficacy study, celecoxib (75 mg/kg/d) was administered orally beginning 3 hours before balloon injury or stent implantation on day 28 and daily for 21 days. Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-2 and -9 (MMPs) expression were quantified in arterial extracts 4 days after balloon injury by Western blot and gelatin zymography. Morphometric analysis and immunostaining for macrophages were performed 21 days after balloon injury. Celecoxib treatment significantly decreased MCP-1 expression (P < 0.01). Neointimal hyperplasia was significantly inhibited by celecoxib in both balloon injury and stent models (0.49 +/- 0.20 versus 0.70 +/- 0.35 mm2 from balloon injury model, P < 0.05, and 0.81 +/- 0.25 versus 1.69 +/- 0.43 mm2 from stent model, P < 0.05), accompanied by reduced macrophage infiltration. We conclude that celecoxib decreases the inflammatory response and intimal hyperplasia following vascular injury, possibly through inhibition of MCP-1 expression, implying a pivotal role of inflammation in the pathogenesis of restenosis.

Celecoxib: a specific COX-2 inhibitor with anticancer properties.

In addition to the well-established pathophysiological role that COX-2 plays in inflammation, recent evidence implies that this isoform may also be involved in multiple biologic events throughout the tumorigenic process. Many epidemiological studies demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of a wide range of tumors. Further, COX-2 is chronically overexpressed in many premalignant, malignant, and metastatic human cancers, and levels of overexpression have been shown to significantly correlate to invasiveness, prognosis, and survival in some cancers. Pharmacological studies consistently demonstrate that COX-2 inhibitors dose-dependently inhibit tumor growth and metastasis in various relevant animal models of cancer. Importantly, several investigators have also shown COX-2 inhibitors may act additively or synergistically with currently used cytotoxics and molecularly targeted agents. Here we present a broad overview of the growing evidence that COX-2 plays a pivotal role throughout oncogenesis and summarize the rationale to explore the use of COX-2 inhibitors for the prevention and/or treatment of cancer as a single agent or in combination with current anticancer modalities.

Chemotherapeutic efficacy of topical celecoxib in a murine model of ultraviolet light B-induced skin cancer.

Over a million nonmelanoma skin cancer cases will be reported in the United States this year alone. Currently the primary form of treatment for these types of skin tumors is excision. However, excision of the initial lesion may not be curative because almost 50% of patients with one nonmelanoma skin cancer lesion develop another tumor within the next 5 yr at the site or adjacent to the site of excision. As with other types of epithelial based cancers, there is mounting evidence for the role of cyclooxygenase-2 (COX-2) and its products, particularly prostaglandin E(2) (PGE(2)), in the development of nonmelanoma skin cancer. To avoid the excision process, the present study was designed to evaluate the possible chemotherapeutic effect of directly treating established tumors with a topical formulation of the specific COX-2 inhibitor celecoxib. Skh/hr hairless mice were irradiated three times per wk for 16 wk to induce tumor formation. The mice were then divided into two groups and treated topically with either 500 microg celecoxib or the vehicle for 6 wk. Our results demonstrated that although topical treatment with celecoxib was not able to induce regression of established tumors, it did prevent new tumor formation after the onset of photocarcinogenesis. Although further studies are warranted, these data suggest that topical celecoxib treatment may prove to be effective in preventing the recurrence of tumors at the site of nonmelanoma skin cancer excision.

Inhibition of cutaneous ultraviolet light B-mediated inflammation and tumor formation with topical celecoxib treatment.

Inflammation, which includes the release of growth factors, proinflammatory cytokines and prostaglandins, the infiltration and activation of inflammatory cells, and the induction of oxidative DNA damage, is known to play a role in cancer development. The combination of damage to the skin resulting from chronic ultraviolet light B (UVB) exposure itself and the inflammatory response it induces is a major source of skin cancer development. Cyclooxygenase-2 (COX-2), an inflammatory enzyme responsible for the production of prostaglandins, is now implicated in the development of epithelial cancers, including squamous cell carcinoma in the skin. Previous work conducted in our laboratory has shown that topical treatment with celecoxib following UVB irradiation inhibits several parameters of acute inflammation, including vascular permeability, the infiltration and activation of neutrophils, and the production of prostaglandin E(2) (PGE(2)). The present studies expanded these observations, demonstrating the ability of topical celecoxib to inhibit acute oxidative damage. In addition, long-term studies illustrate the effectiveness of topical treatment with this drug in reducing chronic inflammation and UVB-induced papilloma/carcinoma formation. This data provides compelling evidence to explore the clinical efficacy of topically applied COX-2 inhibitors for the prevention of human skin cancers.