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

Abstract

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, H 2-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 μL 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 μg/mL) and OVCAR-3 (43 and 94 μg/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).

Natural Phenolic Acid, Product of the Honey Bee, for the Control of Oxidative Stress, Peritoneal Angiogenesis, and Tumor Growth in Mice

“…Tumors in experimental animals or in human body are known to affect many functions of the vital organs. Ascites is a prognostic sign of advanced cancer stage and their inflammatory infiltrate cells and cytokines may affect many functions of the vital organs, especially the liver, kidney, and spleen, even when the site of the tumor does not interfere directly with organ function [13,41,42]. EAT cell inoculation into the mice causes changes in the balance of the antioxidant/oxidative stress system both in EAT and liver tissue [42].…”

“…It has been demonstrated that GA and CA have antioxidant, anti-inflammatory, anti-mutagenic, anti-carcinogenic, anti-neoplastic, and apoptotic activities [3,8,9]. Furthermore, GA and CA have also been shown to suppress cell viability, proliferation, invasion, and angiogenesis in many human and animal cancer cell lines and in animal models [3,[10][11][12][13][14][15]. Thus, Liu et al [16] have shown that GA selectively induces apoptosis in pancreatic cancer cells without affecting the survival of normal cells, whereas Ho and colleagues [17] have shown that GA inhibits gastric cancer cell growth by modulating the levels of MMP-2 and -9 and cytoskeletal reorganization.…”

Functional Characterization of the Lin28/let-7 Circuit during Forelimb Regeneration inAmbystoma mexicanumand its Influence on Metabolic Reprogramming

“…These dyes stain the nuclei in blue-purple, and the cytoplasm with different shades of pink (Varela-Rodríguez et al, 2020). Tissue sections were first post-fixed with 10% paraformaldehyde for 5 minutes and rinsed with tap water.…”

Functional Characterization of the Lin28/let-7 Circuit During Forelimb Regeneration in Ambystoma mexicanum and Its Influence on Metabolic Reprogramming

“…These dyes stain the nuclei in blue-purple, and the cytoplasm with different shades of pink (Varela-Rodríguez et al, 2020). Tissue sections were first post-fixed with 10% paraformaldehyde for 5 min and rinsed with tap water.…”