Omega-3 lipid metabolites as mediators of metformin's anti-proliferative effect in ovarian cancer
Udumula MP, Dimitrova I, Sakr S, Buekers TE, Giri S, and Rattan R. Omega-3 lipid metabolites as mediators of metformin's anti-proliferative effect in ovarian cancer. Gynecologic Oncology 2020; 159:124.
Objective: Metformin is being repurposed for treatment of gynecologic malignancies and other cancers. It is known to alter the cancer cell metabolism, primarily the energy metabolism. Our aim was to identify and test the preclinical efficacy of the prominent metabolite changes occurring in response to metformin treatment in ovarian cancer cell lines.
Method: Three human ovarian cancer cell lines (A2780, C200, and SKOV3IP) treated with metformin (10 mM) for 48 hours were subjected to untargeted global metabolomics by ultra-high-performance liquid chromatography and gas chromatography mass spectroscopy. Statistical and bioinformatics analyses were performed. Five ovarian cancer cell lines (A2780, C200, SKOV3IP, ID8, and OVCAR5) with different genetic makeups and characteristics were treated with varying doses of omega-3 metabolites (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) (12.5–200 uM) with or without carboplatin. Cell survival was assayed by MTT and clonogenic assay (12.5–100 uM). SKOV3 and CaoV3 xenograft models were used for testing the preclinical efficacy of DHA and EPA.
Results: Under metformin treatment, the 3 cell lines revealed 57 common altered metabolites, of which 30 had consistent direction change. The enrichment analysis of the commonly upregulated metabolites indicated a universal increase of the omega-3 biosynthetic pathway, including alpha-linolenic and linoleic acid metabolism (P < 0.001). Treatments with EPA or DHA, the most common lipids from the pathway, resulted in a significant dose-dependent inhibition of proliferation in all 5 cell lines (P < 0.001). EPA and DHA potentiated carboplatin cytotoxicity in all cell lines (P < 0.05). Significant inhibition of colony formation was also noted with EPA and DHA (P < 0.01). Treatment with EPA and DHA significantly improved the survival of mice bearing SKOV3 and CaOv3 xenograft tumors (P < 0.01).
Conclusion: Metformin treatment resulted in increase of omega-3 fatty acid metabolism. Both EPA and DHA, metabolites of the pathway, inhibited ovarian cancer cell proliferation alone and in combination with carboplatin, as well as increased survival in ovarian cancer mouse models. Thus, the cytotoxic effect of metformin may be partially mediated through upregulation of omega-3 lipids.