Anti-cancer and analgesic effects of resolvin D2 in oral squamous cell carcinoma Yi Ye a, b, * , Nicole N. Scheff a , Daniel Bernab  e a , Elizabeth Salvo a , Kentaro Ono a , Cheng Liu c , Ratna Veeramachaneni a , Chi T. Viet a, b , Dan T. Viet a , John C. Dolan a, d , Brian L. Schmidt a, b a Bluestone Center for Clinical Research, College of Dentistry, USA b Department of Oral and Maxillofacial Surgery, College of Dentistry, USA c Head and Neck Pathology, Langone Medical Center, USA d Department of Orthodontics, New York University, New York, NY, USA article info Article history: Received 14 February 2018 Received in revised form 23 June 2018 Accepted 11 July 2018 Keywords: Oral cancer Squamous cell carcinoma Pain Inflammation Resolvin abstract Oral cancer is often painful and lethal. Oral cancer progression and pain may result from shared path- ways that involve unresolved inflammation and elevated levels of pro-inflammatory cytokines. Resolvin D-series (RvDs) are endogenous lipid mediators derived from omega-3 fatty acids that exhibit pro- resolution and anti-inflammatory actions. These mediators have recently emerged as a novel class of therapeutics for diseases that involve inflammation; the specific roles of RvDs in oral cancer and asso- ciated pain are not defined. The present study investigated the potential of RvDs (RvD1 and RvD2) to treat oral cancer and alleviate oral cancer pain. We found down-regulated mRNA levels of GPR18 and GPR32 (which code for receptors RvD1 and RvD2) in oral cancer cells. Both RvD1 and RvD2 inhibited oral cancer proliferation in vitro. Using two validated mouse oral squamous cell carcinoma xenograft models, we found that RvD2, the more potent anti-inflammatory lipid mediator, significantly reduced tumor size. The mechanism of this action might involve suppression of IL-6, C-X-C motif chemokine 10 (CXCL10), and reduction of tumor necrosis. RvD2 generated short-lasting analgesia in xenograft cancer models, which coincided with decreased neutrophil infiltration and myeloperoxidase activity. Using a cancer super- natant model, we demonstrated that RvD2 reduced cancer-derived cytokines/chemokines (TNF-a, IL-6, CXCL10, and MCP-1), cancer mediator-induced CD11b þ Ly6G  myeloid cells, and nociception. We infer from our results that manipulation of the endogenous pro-resolution pathway might provide a novel approach to improve oral cancer and cancer pain treatment. © 2018 Elsevier Ltd. All rights reserved. 1. Introduction Oral squamous cell carcinoma (SCC) is the most common oral malignancy (Wu et al., 2011). Survival of oral SCC patients has modestly improved in the past few decades; recurrence is common (Hunter et al., 2005; Ran and Yang, 2017). Approximately half of all oral SCC patients treated with surgery, chemotherapy, or radiation therapy will be cured. Outside of survival, pain is the primary concern of oral cancer patients (Benoliel et al., 2007; Epstein et al., 2007; Viet and Schmidt, 2012). Oral cancer pain usually becomes more severe with disease progression (Benoliel et al., 2007). Ter- minal oral SCC patients often experience excruciating pain during the final months of life (Benoliel et al., 2007). Ineffective pain control correlates positively with poor outcome and diminished quality of life in oral SCC patients (Reyes-Gibby et al., 2014; Viet and Schmidt, 2012). Chronic inflammation is a hallmark of oral SCC (Choi and Myers, 2008; Feller et al., 2013a; Patel et al., 2016; Wu et al., 2011). Acute inflammation is typically self-limited, initiated by pro- inflammatory cytokines and actively resolved by specialized lipid mediators (i.e., pro-resolution, anti-inflammatory mediators) that return inflamed tissues to homeostasis (Ji et al., 2011; Prevete et al., 2017a; Serhan et al., 2008). These specialized pro-resolving medi- ators are derived from u-3 or u-6 essential polyunsaturated fatty * Corresponding author. Bluestone Centre for Clinical Research, New York Uni- versity, College of Dentistry, 421 First Avenue, 231W, New York, NY,10010, USA. E-mail address: yy22@nyu.edu (Y. Ye). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm https://doi.org/10.1016/j.neuropharm.2018.07.016 0028-3908/© 2018 Elsevier Ltd. All rights reserved. Neuropharmacology 139 (2018) 182e193