NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase

Abstract

Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin’s potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.

Pharmacological Utility of PPAR Modulation for Angiogenesis in Cardiovascular Disease

“…Aspirin is one of the most frequently used drugs worldwide and is considered to be effective in the prevention of cardiovascular disease, mainly through its antithrombotic effects (reviewed in [107]). Additionally, it reduces cancer risk and mortality (reviewed in [108]). PPARα has recently been identified as a receptor for aspirin in the neuronal system [109].…”

The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics

“…In addition to its typical therapeutical effects, some selective COX-2 inhibitors have chemopreventive and chemotherapeutic effects [ 180 ]. The mechanism of action of celecoxib to induce apoptosis could be independent of COX-2 inhibition, and rather the apoptosis may be due to the activation of caspase-8 and -9 with Bid cleavage and the loss of mitochondrial membrane potential, using as a possible target NF-κβ [ 181 ].…”

Acetylsalicylic Acid–Primus Inter Pares in Pharmacology

“…The first relation between ASA and cancer was reported in 1971 [ 137 ]. ASA is not only used for cancer prevention [ 138 , 139 , 140 ], but also administered for adjuvant cancer therapy ( Figure 4 , Table 2 ) [ 141 , 142 ]. Over the last several decades studies have proven that ASA can act in different types of cells such as epithelial cells, tumor cells, endothelial cells, platelets and immune cells.…”