5 research outputs found
A patient perspective on applying intermittent fasting in gynecologic cancer
OBJECTIVE: Researchers sought patient feedback on a proposed randomized controlled trial (RCT) in which gynecological cancer patients would modify their diets with intermittent fasting to gain insight into patients\u27 perspectives, receptivity, and potential obstacles. A convenience sample of 47 patients who met the inclusion criteria of the proposed RCT provided their feedback on the feasibility and protocols of the RCT using a multi-method approach consisting of focus groups (n = 8 patients) and surveys (n = 36 patients).
RESULTS: Patients were generally receptive to the concept of intermittent fasting, and many expressed an interest in attempting it themselves. Patients agreed that the study design was feasible in terms of study assessments, clinic visits, and biospecimen collection. Feedback on what could facilitate adherence included convenient appointment scheduling times and the availability of the research team to answer questions. Regarding recruitment, patients offered suggestions for study advertisements, with the majority concurring that a medical professional approaching them would increase their likelihood of participation
Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo
Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin\u27s antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers
Ovarian cancer modulates the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells via glutamine metabolism
OBJECTIVE: Immature CD11b(+)Gr1(+) myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study\u27s objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells.
METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti PD1 mAb. The treatment effect was assessed by survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies.
RESULTS: Depletion of Gr1(+) immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. These findings, in addition to the adoptive transfer studies, validated the role of immunosuppressive CD11b(+)Gr1(+) myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironment produced both recruitment and regulatory factors for immunosuppressive CD11b(+)Gr1(+) myeloid cells. CD11b(+)Gr1(+) myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted mainly by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found be the most significantly elevated gene in tumor primed myeloid cells. Inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression, and function in myeloid cells.
CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b(+)Gr1(+) myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in those immunosuppressive myeloid decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer
Calorie restriction for ovarian cancer reduction
Objective: Dietary interventions are attractive as inexpensive supportive anticancer therapies. Calorie restriction is an established tumor preventive regimen, reducing systemic inflammation and growth factor signaling, as well as improving metabolic markers in the tumor. The aim of our study was to determine the effect of calorie restriction on ovarian cancer outcome.
Method: Female B6 mice were fed either ad libitum or underwent a 30% calorie restriction. After 5 weeks, mouse epithelial ovarian cancer (EOC) ID8 cells (5 million cells) were injected intraperitoneally. Tumor growth was monitored by in situ luciferases guided imaging, followed by pathological determination of tumors at 8 weeks. Changes in growth factors/cytokines were determined by ELISA, and immune response was measured by flow cytometry analysis.
Results: The mice on calorie restriction displayed decreased EOC burden in contrast to mice fed ad libitum (P \u3c 0.01). The mice on calorie restriction exhibited increased survival (median survival 100 days) in contrast to mice fed ad libitum (median survival 70 days, P \u3c 0.01). The calorie-restricted mice showed a significant reduction in levels of insulin, leptin, MCP-1, VEGF, and IL-6 (P ranging from 0.5 to 0.01). In addition, calorie-restricted mice had increased frequency of T cells (CD4, CD8, and NKT cells) and decreased frequency of macrophages (P \u3c 0.05).
Conclusion: Our study suggests that calorie restriction can suppress ovarian cancer growth and is associated with modulation of inflammatory and immune microenvironment, suggesting the promise of calorie restriction and its mimetics as supportive anticancer therapies
Omega-3 lipid metabolites as mediators of metformin\u27s anti-proliferative effect in ovarian cancer
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 \u3c 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 \u3c 0.001). EPA and DHA potentiated carboplatin cytotoxicity in all cell lines (P \u3c 0.05). Significant inhibition of colony formation was also noted with EPA and DHA (P \u3c 0.01). Treatment with EPA and DHA significantly improved the survival of mice bearing SKOV3 and CaOv3 xenograft tumors (P \u3c 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