Investigating the capability of metformin to increase the efficacy of oncolytic herpesvirus in ovarian cancer

Background: Ovarian cancer (OC) is common, and frequently fatal, gynecological malignancy lacking distinct symptoms, resulting in late-stage diagnosis and difficult treatment. Although direct causes of OC are unknown, an association between OC and Type Two Diabetes (T2D) exists. Individuals with T2D, characterized by chronic metabolic dysregulation, are more likely to develop cancer later in life than those without. Recently, the effects established by anti-T2D medications, traditionally used to manage hyperglycemia, have been examined within the scope of metabolically reprogramming cancer cells to sensitize them for further treatment. Metformin is a low-cost medication currently being studied as a chemotherapy adjuvant in numerous types of cancer, given its ability to manipulate cellular glucose metabolism, proliferation pathways, and promote apoptosis. Several preclinical studies have demonstrated metformin's ability to decrease inflammation in diseases other than T2D, suggesting it influences immune responses, thus creating the possibility of a novel treatment option to increase the efficacy of current immunotherapies, such as oncolytic virotherapy. Oncolytic viruses are biological anti-tumor agents capable of selectively infecting cancer cells, eliciting an anti-cancer immune response in patients. We hypothesize that metformin dysregulates glucose metabolism in OC cells, decreasing cell viability and increasing the efficacy of oncolytic virus HSV1716. This hypothesis was tested human and mouse ovarian cancer cell lines. Methods : Mouse ovarian cancer cells (ID8, BPPNM) or human ovarian cancer cells (A2780, SKOV3) were grown in MEM 10% FBS. For some experiments, high (5 g/l) and normal (1 g/l) glucose MEM was used. Cells were treated with 50, 25, 12.5, and 6.25 mM of metformin in 2D and 3D environments. Scratch assays were used to monitor effects on cell motility. All experiments were monitored at 24-,48- and 72- hours post-treatment. Finally, metformin was administered in conjunction with HSV-1716 at varying concentrations to OC cells. Results and Conclusions : We observed that metformin decreased cell viability and motility, and spheroid growth as determined by MTS assays, flow cytometry analysis and light microscopy. The effect of the drug was further exacerbated by virus treatment, indicating that a combination of both therapeutic strategies is feasible. Further investigations using in vivo OC mouse models will help determine the effects of metformin on immunosuppressive cell populations in the OC tumor microenvironment and its capacity to increase oncolytic efficacy in vivo.