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.
Highlights
Inflammation as a fundamental response to injury has been recognized for thousands of years
It is clear that nonsteroidal anti-inflammatory drugs (NSAIDs) prevent various human cancers and that they act on multiple molecular targets, of which COX-2 is only one
The third biochemical pathway leads to the formation of epi-lipoxins, or aspirin-triggered lipoxins (AT-Ls), which occur during cell–cell interactions, such as between endothelial cells and polymorphonuclear leukocytes (PMNs)
Summary
Inflammation as a fundamental response to injury has been recognized for thousands of years. Aspirin is the only NSAID that covalently modifies the COX enzymes It acetylates the catalytic subunits of the COX enzymes by accessing the enzymatic active site via the arachidonic acid (AA)-binding channel [26,27]. Aspirin acetylates serine 530 of the cyclooxygenase-1 (COX-1, constitutive) enzyme [26]; the interposition of the bulky acetyl residues prevents AA from accessing and binding to the enzymatic active site. This inhibition of AA binding blocks COX-1 from synthesizing prostaglandins (PGs) [27]. Aspirin inhibits TxA2 synthesis, resulting in a decreased chance of thrombosis or thrombotic events
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