Document resource
Background Ovarian cancer is one of the most prevalent gynecologic malignancies worldwide, being the fifth leading cause of cancer-related deaths among women with a dismal five-year survival rate. There is an association between people with diabetes and an increased risk of developing cancer later in life. Several studies have evaluated combining type-2 diabetes mellitus (T2DM) drugs with chemotherapy agents since inhibiting glucose metabolism could potentiate cancer treatment by depleting the tumor cells’ energy source. Oncolytic viruses kill tumor cells leaving healthy cells unharmed and activating an antitumor immune response. We hypothesize that targeting tumor cells with TD2M drugs together with oncolytic virotherapy could lead to a better antitumor response. Here we investigated the effect of several T2DM drugs (metformin, rosiglitazone, canagliflozin and sitagliptin) on mouse and human ovarian cancer cells in vitro, and the effect of this treatment on the activity of oncolytic DNA and RNA viruses: herpesvirus (HSV-1716) and reovirus (type 3 Dearing).Methods Mouse ID8 and BPPNM (p53−/−R172HBrca1−/−Pten−/−Nf1−/−MycOE), and human A2780 and SKOV3 ovarian cancer cells were treated with different concentrations of metformin, rosiglitazone, canagliflozin or sitagliptin in 2D and 3D environments and cell viability (monolayers) or spheroid size (3D cultures) tested at different times post-treatment (24-, 48- and 72-hours post-treatment). In addition, scratch assays were performed on treated cells to define the efficacy of the drugs on cell mobility (24-, 48- and 72-hours post-treatment). Finally, drugs were combined with oncolytic viruses to define the effect of the treatment on cell viability at different time points and viral concentrations.Results Metformin and Canagliflozin were able to significantly decrease the viability, mobility capacity and ability to generate spheroids in all cell lines evaluated, while the effect of rosiglitazone and sitagliptin was minimal even at the highest concentrations assessed (1200 µM for both drugs). Oncolytic virus activity on these cell lines was augmented in 2D environments only in the presence of metformin and sitagliptin, albeit the latter showed no effect on cell viability by itself. Interestingly, the drugs were also able to increase the capacity of the viruses to affect spheroid cultures, as determined by analyzing spheroids by light microscopy and ImageJ.Conclusions Preliminary data indicate that metformin and sitagliptin are appropriate candidates to perform in vivo studies in mouse models of ovarian cancer in combination with oncolytic virotherapy.