Anti-cancer and analgesic effects of resolvin D2 in oral squamous cell carcinoma

Ye, Yi; Scheff, Nicole N.; Bernabé, Daniel Galera; Salvo, Elizabeth; Ono, Kentaro; Liu, Cheng Z.; Veeramachaneni, Ratna; Viet, Chi T.; Viet, Dan T.; Dolan, John C.; Schmidt, Brian L.

doi:10.1016/j.neuropharm.2018.07.016

Cited by 66 publications

(70 citation statements)

References 61 publications

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“…We further characterized the role of ALX/ FPR2 in aspirin's anticancer activity by systemically treating established tumors (10 6 LLC cells/mouse) in genetically engineered ALX/FPR2 knockout (KO) or wild-type (WT) mice with low-dose aspirin or vehicle. Consistent with the antitumor activity of resolvins (23,(30)(31)(32)(33)(34), LLC tumor growth was accelerated in the ALX/FPR2 KO mice compared with WT mice (Fig. 2C).…”

Section: Resultssupporting

confidence: 74%

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Gilligan

Gartung

Sulciner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

129

113

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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-LXA 4 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. metabolomics | eicosanoids | resolvins | inflammation | metastasis M ore than 80 million aspirin tablets are consumed every year (1). Epidemiologic evidence suggests that the nonsteroidal anti-inflammatory drug (NSAID) aspirin reduces the risk and incidence of cancer and also prolongs survival when administered postdiagnosis (2). While initial studies have focused on colorectal cancers, low-dose aspirin has also demonstrated consistent antitumor activity in other cancers, including lung, breast, prostate, and metastatic cancers (3,4). Studies have also identified survival and chemopreventive benefits of low-dose aspirin following cytotoxic therapy (e.g., radiation, chemotherapy) or surgical tumor resection (5, 6). Compelling evidence of aspirin's anticancer activity stems from patients receiving low-dose aspirin for cardioprevention, in which a substantial fraction (20-30%) benefits from a decrease in cancer incidence (7). In contrast, several studies show that neither nonaspirin NSAIDs nor acetaminophen are associated with a reduced risk of cancer or chemopreventive activity (8,9). While the known anti-inflammatory activity of aspirin offers a generic rationale, the unique antitumor mechanisms of aspirin compared with other NSAIDs remain poorly understood. Importantly, the use of low-dose aspirin in cancer patients is limited by adverse side effects, such as gastrointestinal bleeding and hemorrhagic stroke, that necessitate hospitalization (10).The study of anti-inflammatory mechanisms in cancer has traditionally focused on the suppression of proinflammatory mediators, such as cytokines, eicosanoids, and enzymes (2). Cycloo...

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Section: Resultssupporting

confidence: 74%

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Gilligan

Gartung

Sulciner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

129

113

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“…The SPM superfamily consists of potent immunoresolvent agonists derived from omega-3 fatty acids (e.g., resolvins, protectins, and maresins) as well as arachidonic acid (e.g., lipoxins) (12,43,(45)(46)(47). Resolvins, lipoxins, and aspirin-triggered SPMs exhibit antitumor activity by promoting the clearance of therapy-generated tumor cell debris and counterregulating proinflammatory cytokines (9,(48)(49)(50)(51). Interestingly, unlike other synthetic nonsalicylate NSAIDs, aspirin irreversibly acetylates COX-2 and converts its enzymatic activity to produce aspirin-triggered SPMs.…”

Section: Resultsmentioning

confidence: 99%

“…Since LXA 4 is an SPM (12), we reasoned that the balance of inflammation regulation may be tipped toward resolution, thereby either enhancing or recapitulating the antiinflammatory and proresolving activity of ketorolac. Indeed, SPMs, such as lipoxins and resolvins, possess potent antitumor activity in experimental models (9,(48)(49)(50)(51)62).…”

Section: Resultsmentioning

confidence: 99%

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Panigrahy¹,

Gartung²,

Yang³

et al. 2019

Journal of Clinical Investigation

114

113

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“…A paradigm shift is emerging in our understanding of the pathogenesis of pathological inflammation which not only results from the persistent activation of inflammatory signals, but also the failure of engaging pro-resolving mechanisms including clearance of cell death “debris” and counter-regulation of pro-inflammatory cytokines ( Serhan, 2014 ; Serhan & Levy, 2018 ). Experimental and human studies suggest that cancer progression results from the “failure to clear debris” after chemotherapy, radiation, or surgery ( Chaurio et al, 2013 ; da Silva-Jr, Chammas, Lepique, & Jancar, 2017 ; Ford et al, 2015 ; Gartung et al, 2019 ; Gilligan et al, 2019 ; Gunjal et al, 2015 ; Huang et al, 2011 ; Panigrahy et al, 2019 ; Revesz, 1956 ; Sulciner et al, 2018 ; Ye et al, 2018 ). Thus, failure to engage resolution of inflammation mechanisms including clearance of debris may lead to carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, failure to engage resolution of inflammation mechanisms including clearance of debris may lead to carcinogenesis. Differentiating between suppression and resolution of inflammation is critical to mechanistic studies in inflammation-driven diseases including cancer ( Fishbein et al, 2020 ; Gilligan et al, 2019 ; Kuang, Hua, Zhou, & Yang, 2016 ; Panigrahy et al, 2019 ; Serhan, 2014 ; Shan et al, 2020 ; Sulciner et al, 2018 ); Ye et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Carcinogenesis: Failure of resolution of inflammation?

Fishbein

Hammock

Serhan

et al. 2021

Pharmacology & Therapeutics

138

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Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.

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Anti-cancer and analgesic effects of resolvin D2 in oral squamous cell carcinoma

Cited by 66 publications

References 61 publications

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

Carcinogenesis: Failure of resolution of inflammation?

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