Aspirin-triggered proresolving mediators stimulate resolution in cancer

Significance Strong epidemiologic evidence indicates that aspirin is a powerful antitumorigenic agent. We now demonstrate that aspirin-triggered resolvins achieve the antitumor and chemopreventive activity of aspirin without toxicity, identifying a mechanism for aspirin’s anticancer activity. Our results suggest that differentiating between suppression and resolution of inflammation is highly relevant in cancer biology, revealing a class of endogenous antitumor mechanisms. These results have pivotal implications for cancer therapy and chemoprevention; unlike anti-inflammatory drugs, aspirin-triggered resolvins are active at nanogram doses and are not immunosuppressive. The antitumorigenic activity of aspirin-triggered resolvins may be harnessed to “mimic” aspirin without incurring aspirin-induced toxicity, such as bleeding, to contain minimal residual disease. Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin’s broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin’s anticancer activity.