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

2020; Elsevier BV; Volume: 128; Linguagem: Inglês

10.1016/j.biopha.2020.110247

1950-6007

Rafael Carlos Ferreira, Tatianne Mota Batista, Sâmia Sousa Duarte, Daiana Karla Frade Silva, Thaís Mangeon Honorato Lisboa, Raquel Fragoso Pereira Cavalcanti, Fagner Carvalho Leite, Vivianne Mendes Mangueira, Tatyanna Kélvia Gomes de Sousa, Renata Albuquerque de Abrantes, Emmely Trindade, Petrônio Filgueiras de Athayde-Filho, Maria Cláudia Rodrigues Brandão, Karina Carla de Paula Medeiros, Davi Felipe Farias, Marianna Vieira Sobral,

Ginger and Zingiberaceae research

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.