A novel piperine analogue exerts in vivo antitumor effect by inducing oxidative, antiangiogenic and immunomodulatory actions

• Published in: Biomedicine & pharmacotherapy 2020-08, Vol.128, p.110247, Article 110247
• Main Authors: Ferreira, Rafael Carlos, Batista, Tatianne Mota, Duarte, Sâmia Sousa, Silva, Daiana Karla Frade, Lisboa, Thaís Mangeon Honorato, Cavalcanti, Raquel Fragoso Pereira, Leite, Fagner Carvalho, Mangueira, Vivianne Mendes, Sousa, Tatyanna Kélvia Gomes de, Abrantes, Renata Albuquerque de, Trindade, Emmely Oliveira da, Athayde-Filho, Petrônio Filgueiras de, Brandão, Maria Cláudia Rodrigues, Medeiros, Karina Carla de Paula, Farias, Davi Felipe, Sobral, Marianna Vieira
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - toxicity; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - toxicity; Carcinoma, Ehrlich Tumor - drug therapy; Carcinoma, Ehrlich Tumor - immunology; Carcinoma, Ehrlich Tumor - metabolism; Carcinoma, Ehrlich Tumor - pathology; Cytokines - metabolism; Male; Mice; Neovascularization, Pathologic; Non-clinical toxicity; Oxidants - chemical synthesis; Oxidants - pharmacology; Oxidants - toxicity; Oxidative Stress; Piperidines - chemical synthesis; Piperidines - pharmacology; Piperidines - toxicity; Piperine analogue; Reactive Oxygen Species - metabolism; Tumor Microenvironment; Zebrafish; Zebrafish - embryology
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110247

[Display omitted] Structural diversity characterizes natural products as prototypes for design of lead compounds. The aim of this study was to synthetize, and to evaluate the toxicity and antitumor action of a new piperine analogue, the butyl 4-(4-nitrobenzoate)-piperinoate (DE-07). Toxicity was evaluated against zebrafish, and in mice (acute and micronucleus assays). To evaluate the DE-07 antitumor activity Ehrlich ascites carcinoma model was used in mice. Angiogenesis, Reactive Oxygen Species (ROS) production and cytokines levels were investigated. Ninety-six hours exposure to DE-07 did not cause morphological or developmental changes in zebrafish embryos and larvae, with estimated LC50 (lethal concentration 50%) higher than 100 μg/mL. On the acute toxicity assay in mice, LD50 (lethal dose 50%) was estimated at around 1000 mg/kg, intraperitoneally (i.p.). DE-07 (300 mg/kg, i.p.) did not induce increase in the number of micronucleated erythrocytes in mice, suggesting no genotoxicity. On Ehrlich tumor model, DE-07 (12.5, 25 or 50 mg/kg, i.p.) induced a significant decrease on cell viability. In addition, there was an increase on ROS production and a decrease in peritumoral microvessels density. Moreover, DE-07 induced an increase of cytokines levels involved in oxidative stress and antiangiogenic effect (IL-1β, TNF-α and IL-4). No significant clinical toxicological effects were recorded in Ehrlich tumor transplanted animals. These data provide evidence that DE-07 presents low toxicity, and antitumor effect via oxidative and antiangiogenic actions by inducing modulation of inflammatory response in the tumor microenvironment.