Maresin 1: A Potent Endogenous Anti-Inflammatory And Pro-Resolving Inhibitor Of Primary Tumor Growth And Metastasis

Background: Inflammation is a recent hallmark of cancer, and chemotherapeutic agents, such as etoposide, cisplatin and paclitaxel, stimulate pro-inflammatory cytokine production by macrophages in the tumor microenvironment. A new direction has emerged in inflammation research with the discovery of endogenous anti-inflammatory and pro-resolving lipid-autacoid mediators derived from omega-3 polyunsaturated fatty acids. These specialized pro-resolving mediators (SPM), including maresin 1, have novel inflammation clearing (‘pro-resolution’) activity without being immunosuppressive. Maresin 1 (Mar1) is a novel endogenous anti-inflammatory and pro-resolving lipid autacoid mediator biosynthesized by human macrophages from endogenous docosahexaenoic acid (DHA). The role of maresin 1 in cancer has not been studied to date. However, we hypothesize that maresin 1 inhibits cancer progression and metastasis by stimulating the resolution of inflammation and down-regulating pro-inflammatory cytokines. Results: Maresin 1 stimulated macrophage phagocytosis of chemotherapy-induced melanoma (A375-SM) cell debris by 117%. The maresin 1 epimer, 7(S)-Mar1, also enhanced macrophage phagocytosis of chemotherapy-induced cell debris by 58%. Maresin 1 stimulated macrophage phagocytosis of apoptotic prostate (PC3M-LN), melanoma (A375-SM), head and neck (HSC-3), and ovarian (HEY) tumor cells by 206%, 32%, 35%, and 13%, respectively, as well as enhanced macrophage phagocytosis of zymosan by 62%. Macrophages, exposed to tumor cells treated with cisplatin, secrete pro-inflammatory cytokines. Mar1 and 7(S)-Mar1 regulated these inflammatory cytokines. Mar1 decreased cisplatin-induced pro-tumorigenic and pro-inflammatory cytokines secreted by macrophages, including: IL-8, IL-6, CXCL1, CCL1, CCL2, CCL5, and Serpin E1. In contrast, 7(S)-Mar1 increased IL-6, CXCL1, CCL2, CCL3, CCL5. Systemic therapy with Mar1 (15 nanogram/mouse/day) for 15-24 days potently inhibited primary melanoma xenografts (A375-SM) and lung metastasis (B16F10) by 75% and 57%, respectively, without toxicity. Conclusions: Maresin 1 inhibits primary tumor growth and metastasis via the stimulation of phagocytosis of apoptotic and chemotherapy-treated tumor cells by macrophages. In addition, maresin 1 reduces tumor inflammation by counter-regulating pro-inflammatory cytokines secreted by macrophages. Our results provide a mechanistic rationale to specifically enhance endogenous resolution processes to complement conventional modalities for cancer treatment. Citation Format: Dayna Mudge, Mark W. Kieran, Diane Bielenberg, Ofra Benny, Jesmond Dalli, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Maresin 1: a potent endogenous anti-inflammatory and pro-resolving inhibitor of primary tumor growth and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1170. doi:10.1158/1538-7445.AM2014-1170