Cyclooxygenase inhibitors: Scope of their use and development in cancer chemotherapy

Abstract

The traditional nonsteroidal anti-inflammatory drugs (NSAIDs) exert their effect by inhibition of cyclooxygenase-1 (COX-1) as well as COX-2 enzymes. As COX-1 is responsible for maintaining normal biological functions, the nonselective inhibition of these enzymes caused side effects including gastrointestinal (GI) problems. Recently developed selective COX-2 inhibitors could reduce these adverse effects, but the evidence of cardiovascular side effects including an increased risk of myocardial infarction began to emerge, and some of the COX-2 inhibitors were eventually withdrawn from the market and this led to the downfall of this research. So, the discovery of novel COX-2 inhibitors with their safety profile became the biggest challenge in pharmaceutical research. However, recent mechanistic and clinical studies revolutionized this area by indicating the fact that COX-2 is involved in apoptosis resistance, angiogenesis, and tumor progression. Epidemiological data suggest that selective COX-2 inhibitors might prevent the development of cancers. Moreover, COX-2 is found to be overexpressed in many cancers thus making it an attractive therapeutic target for the prevention and treatment of a number of malignancies. The purpose of this review is to focus on the medicinal chemistry aspects of COX-2 inhibitors in cancer chemotherapy and recent reports on these inhibitors as anticancer agents. We attempted to cover only the COX inhibitors that showed anticancer activity, although a number of potent COX-2 inhibitors have been reported without their anticancer effects. Furthermore, structure-activity relationships (SAR) of different classes of compounds for COX-2 inhibition as well as anticancer activity, and their future applications are discussed.

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

“…Although the benefit of aspirin for patients with cancer has been widely appreciated, the mechanism behind remains largely unclear. Previous understandings tend to attribute the anticancer potential of aspirin to the inhibition of cyclooxygenase-2 (COX-2), which is upregulated in various cancer cells (10,11). Of note, increasing evidence has suggested that aspirin may exhibit anticancer effects in a COX-independent manner.…”

Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3-alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti-inflammatory activity

“…Phospholipase A2 (PLA 2 ) enzymes cleave membrane bound arachidonate for the conversion into bioactive precursors. AA can be metabolized through COX pathway via a two-step process: the first step involves conversion of AA to prostaglandin G2 (PGG 2 ), a 9,11-endoperoxide-15-hydroperoxide, and in the second step peroxidase reduces PGG 2 to prostaglandin H 2 (PGH 2 ). Specific PG synthases further metabolize PGH 2 to give structurally related bioactive lipids, including PGs PGE 2 , PGD 2 , PGF 2a , prostacycline PGI 2 and thromboxane A 2 (TxA2) [2].…”

“…PGE 2 specifically exerts carcinogenic effects in the human body. It was found that premalignant lesions and established cancers produce excessive quantities of PGE 2 and this enhances tumor cell growth and increases tumor invasiveness [1]. COX-2 is up-regulated in a number of epithelial cancers, including those originating in the colon and rectum, stomach, breast, prostate, and lung [6].…”

“…COX-2 is up-regulated in a number of epithelial cancers, including those originating in the colon and rectum, stomach, breast, prostate, and lung [6]. In the context of cutaneous tissues, increased expression of COX-2 and production of its primary product PGE 2 have been reported to increase cell growth and decrease apoptosis. PGE 2 is also thought to be responsible for different skin cancers, such as squamous cell and basal cell carcinoma [7].…”

Chemoprevention and Novel Treatments of Non-Muscle Invasive Bladder Cancer

“…Studies suggest that cyclooxygenase enzymes may have a key role in carcinogenesis, thus inhibitors have the potential for cancer prevention (Axelsson et al, 2010;Flossmann et al, 2007;Khan & Lee, 2011). Recent studies suggest an important role of COX-2 inhibitors in bladder cancer therapy.…”