Effect of Gallic acid and Myricetin on ovarian cancer models: a possible alternative antitumoral treatment

Background: Ovarian cancer is the leading cause of mortality among malignant gynecological tumors. Surgical resection and chemotherapy with intravenous platinum/taxanes drugs are the treatments of choice, with little effectiveness in later stages and severe toxicological effects. Therefore, this study aimed to evaluate the antineoplastic activity of gallic acid (GA) and myricetin (Myr) administrated peritumorally in Nu/Nu mice xenotransplanted with SKOV-3 cells. Methods: Biological activity of GA and MYR was evaluated in SKOV-3 and OVCAR-3 cells (ovarian adenocarcinomas) by confocal/transmission electron microscopy, PI-flow cytometry, H2-DCF-DA stain, MTT, and Annexin V/PI assays. Molecular targets of compounds were determined with ACD/I-Labs and SEA. Antineoplastic activity was performed in SKOV-3 cells subcutaneously xenotransplanted into female Nu/Nu mice treated peritumorally with 50 mg/kg of each compound (2 alternate days/week) for 28 days. Controls used were paclitaxel (5 mg/kg) and 20 mu L of vehicle (0.5% DMSO in 1X PBS). Tumor lesions, organs and sera were evaluated with NMR, USG, histopathological, and paraclinical studies. Results: In vitro studies showed a decrease of cell viability with GA and Myr in SKOV-3 (50 and 166 mu g/mL) and OVCAR-3 (43 and 94 mu g/mL) cells respectively, as well as morphological changes, cell cycle arrest, and apoptosis induction due to ROS generation (p = 0.05, ANOVA). In silico studies suggest that GA and MYR could interact with carbonic anhydrase IX and PI3K, respectively. In vivo studies revealed inhibitory effects on tumor lesions development with GA and MYR up to 50% (p = 0.05, ANOVA), with decreased vascularity, necrotic/fibrotic areas, neoplastic stroma retraction and apoptosis. However, toxicological effects were observed with GA treatment, such as leukocyte infiltrate and hepatic parenchyma loss, hypertransaminasemia (ALT: 150.7 +/- 25.60 U/L), and hypoazotemia (urea: 33.4 +/- 7.4 mg/dL), due to the development of chronic hepatitis (p <= 0.05, ANOVA). Conclusion: GA and Myr (50 mg/kg) administered by peritumoral route, inhibit ovarian tumor lesions development in rodents with some toxicological effects. Additional studies will be necessary to find the appropriate therapeutic dose for GA. Therefore, GA and Myr could be considered as a starting point for the development of novel anticancer agents.