Adjuvant supplementation of docosahexaenoic acid with 2-deoxyglucose, metformin, and aspirin on cellular metabolism in breast, lung, and prostate tumor cells

A standard treatment for cancer often involves the use of adjuvant supplementation with targeted therapy to maximize tumor suppression. Recent studies have shown that docosahexaenoic acid (DHA; C22:6 n-3), a long chain omega-3 polyunsaturated fatty acid, acts on an array of molecular oncogenes that are often targeted by anti-tumorigenic drugs. After a careful review of DHA’s mechanistic properties, 2-deoxyglucose (2DG), metformin, and aspirin were identified as drugs that share similar molecular targets as DHA. 2DG and metformin both target cellular metabolism by inhibiting intracellular ATP, albeit different mechanisms. 2DG inhibits glycolysis, while metformin targets the mitochondria. Aspirin inhibits inflammation via irreversible acetylation of platelet COX. The current study investigates the effects of DHA in combination with each drug on numerous cancer subtypes to determine if concurrent treatments can synergistically inhibit tumor proliferation. In BT-474 human breast ductal carcinoma, MDA-MB-231 human breast adenocarcinoma, and A549 human lung adenocarcinoma, DHA was shown to enhance the tumor-inhibiting effects of 2DG via intracellular ATP reduction. In contrast, DHA showed no effect with metformin on the same tumor cell lines. With limited studies localizing DHA’s metabolic effects, these results suggest that DHA may have potential selectivity for ATP inhibition via glycolysis. In response to DHA + aspirin, the PC-3 prostate adenocarcinoma and MDA-MB-231 displayed synergistic inhibition of cell viability, while LNCaP prostate carcinoma showed an additive effect. With studies showing DHA’s ability to inhibit endothelial COX, further studies will be done to determine whether the synergistic effects of DHA + aspirin expand to COX expression as well. Moreover, downstream targets of 2DG and metformin will be studied to determine the extent of DHA enhancement on oncogenic targets, such as mTOR, 4EB-P1, and GRB10. The results of this study provide preliminary evidence for the efficacy of adjuvant supplementation with DHA in combination with anti-tumorigenic drugs. With ongoing analysis, the potential for adjuvant nutritional supplementation will allow for additional treatment strategies for future patients. Citation Format: Irvin V. Ma, Michael Mouradian, Andrew R. Cooper, Erika D. Vicente, Ronald S. Pardini. Adjuvant supplementation of docosahexaenoic acid with 2-deoxyglucose, metformin, and aspirin on cellular metabolism in breast, lung, and prostate tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1616.