Abstract 766: Control of lung cancer with aspirin-triggered stimulation of resolution

Abstract

Abstract Objective: To establish aspirin-triggered resolvins as a novel treatment to enhance current cancer therapies through the resolution of inflammation and clearance of cancer therapy-induced tumor cell debris. Background: Inflammation in the tumor microenvironment is now recognized as a strong promoter of tumor growth. Substantial epidemiological evidence suggests that aspirin, which suppresses inflammation, also reduces the risk of cancer. However, the mechanism by which aspirin reduces cancer risk and improves survival remains unclear, and toxicity has limited its clinical use. Low-dose aspirin stimulates the endogenous production of aspirin-triggered (AT) resolvins, novel omega-3 fatty acid-derived pro-resolving lipid autacoid mediators. We recently discovered that resolvins have potent anti-tumor activity, making resolvins potential candidates to mediate the anti-cancer activity of aspirin. Thus, we hypothesize that aspirin's anti-cancer activity is mediated in part by AT-resolvins via novel anti-inflammatory and pro-resolution mechanisms. Methods: Flow cytometry confirmed apoptotic and necrotic lung tumor cell debris following chemotherapy (etoposide) or targeted therapy (erlotinib) treatment in vitro. Macrophage phagocytosis was quantified via Relative Fluorescent Units (RFU). Cytokine levels were quantified via ELISA. Results: AT-resolvins counter therapy-induced debris-stimulated tumor growth and spontaneous lung metastases via enhancing endogenous clearance of tumor debris via macrophages and counter-regulating macrophage cytokine production. Pharmacological and genetic antagonism of the AT-resolvin D1 receptor (ALX/FPR2) neutralized aspirin's anti-cancer activity. Conclusions: AT-resolvins may provide a novel pathway and molecular mechanism to explain how aspirin reduces cancer risk so broadly. These anti-inflammatory and pro-resolving lipid autacoid mediators may complement current therapies for lung cancer with minimal toxicity. Citation Format: Molly M. Gilligan, Megan L. Sulciner, Yael Gus-Brautbar, Sesquile Ramon, Romain A. Colas, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Control of lung cancer with aspirin-triggered stimulation of resolution. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 766.