Dual COX-2/TNF-α Inhibitors as Promising Anti-inflammatory and Cancer Chemopreventive Agents: A Review

Cyclooxygenases (COX) play a pivotal role in inflammation and are responsible for the production of prostaglandins (PGs). Two types of COXs have been identified as key biological targets for drug design: Constitutive COX-1 and inducible COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) target COX-1, while selective COX-2 inhibitors are designed for COX-2. These COX isoforms are involved in multiple physiological and pathological pathways throughout the body. Overproduction of tumor necrosis factor-alpha (TNF-α) plays a role in COX-2's inflammatory activity. Tumor necrosis factor-alpha can contribute to cardiac fibrosis, heart failure, and various cancers by upregulating the COX-2/PGE2 axis. Therefore, suppressing COX activity has emerged as a potentially effective treatment for chronic inflammatory disorders and cancer. This review explores the mechanisms of TNF-α-induced COX-2/PGE2 expression, a significant pathophysiological feature of cancer development. Furthermore, we summarize chemical compounds with dual COX-2/TNF-α inhibitory actions, providing an overview of their structure-activity relationship. These insights may contribute to the development of new generations of dual-acting COX-2/TNF-α inhibitors with enhanced efficacy.