Abstract 840: High levels of hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)) in fish oil induce resistance to chemotherapy <i>in vivo</i>
Authors: Laura G.M. Daenen, Jeanine M.L. Roodhart, Julia M. Houthuijzen, Edwin C.A. Stigter, Johan Gerrits, Arjan B. Brenkman, Emile E. Voest
Journal: Cancer Research (2012)

Abstract Environment-mediated resistance to chemotherapy is emerging as a cause of treatment failure. We recently discovered that two fatty acids, 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), induced resistance to a broad spectrum of chemotherapeutics in mice. These fatty acids were produced by mesenchymal stem cells upon platinum stimulation, and were therefore called platinum-induced fatty acids (PIFAs; Roodhart et al, Cancer Cell 2011). Fish oil, a complex, non-standardized mixture of fatty acids, was also shown to contain high levels of these PIFAs. Fish oil supplements are commonly used by cancer patients due to their perceived positive health effects. First, to determine the percentage of cancer patients taking fish oil supplements, a questionnaire was handed out at the UMC Utrecht medical oncology department. In an interim analysis, 12% of responders (11/90) were found to use fish oil supplements, the majority of whom continued supplementation during chemotherapy (82%). Second, we analyzed 5 commercially available fish oils for 16:4(n-3) content by ultra-high pressure liquid chromatography coupled to Orbitrap mass spectrometry. Even though 16:4(n-3) values differed, all tested fish oils contained significant amounts of the resistance-inducing PIFA. Concentrations ranged between 0.1 - 6.5 μM 16:4(n-3). We previously determined that as little as 25 nM purified 16:4(n-3) was sufficient to induce chemoresistance in mice. Here, we show that fish oils abundant in 16:4(n-3) interfered with chemotherapy actions in BALB/c mice bearing subcutaneous C26 tumors. Fish oil alone, administered by oral gavage, did not alter tumor volume compared to untreated mice. However, a single oral administration of each of three different fish oils together with intraperitoneal cisplatin therapy induced potent chemoresistance (tumor volume on day 4 after fish oil and chemotherapy was 222%, 223% and 246% compared to tumor volume after cisplatin alone). These results were confirmed in LLC-bearing C57Bl/6 mice. Finally, the fish oil containing the highest 16:4(n-3) level (6.5 μM) was tested for dose dependency by oral administration of 100, 10, 1 and 0.1 αl. As little as 1 αl of this fish oil was sufficient to induce resistance to cisplatin. On day 4, tumor volumes were 118±44 mm3 for vehicle-treated mice, 41±16 mm3 for cisplatin-treated and 94±63 mm3 for mice treated with cisplatin + 1 αl of fish oil (p 0.02). Concluding, commercially available fish oils contained variable levels of resistance-inducing PIFA 16:4(n-3). In clinically relevant doses, fish oil induced resistance to chemotherapy in mice. This implicates that fish oil use can interfere with chemotherapy outcome. 12% of cancer patients use fish oil, urging the need for clinical studies to determine the effects of fish oil intake on PIFA concentrations in human plasma, and on response to chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 840. doi:1538-7445.AM2012-840