Toxicidade e potencial antitumoral do análogo da piperina 2-oxo-2-(4-nitrofenilamina)-piperinoato de etila em modelo experimental de tumor ascítico de ehrlich

• Autor(a) principal: Santos, Jephesson Alex Floriano dos
• Data de Publicação: 2017
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UFPB
• Texto Completo: https://repositorio.ufpb.br/jspui/handle/123456789/12320
• topic: Piperina; Atividade antitumoral; Toxicidade; Antitumor activity; Piperine; Toxicity; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA

Cancer is a worldwide public health problem, associated to an elevated rate of failure in therapy, which is related to aspects such as effectiveness, toxicity, pharmacokinetics and resistance by tumor cells. In this context, natural products still have a big part as prototypes to the synthesis of new drug candidates. The piperine is an amide alkaloid, isolated from species of Piper, which shows antitumor activity, however it has significant toxicity. In order to potentiate its activity and reduce the toxicity, several unpublished analogues are being studied, among them the 2-oxo-2-(4-nitrophenylamine) ethyl piperinoate (HE-02). This work aimed to investigate the antitumor activity as well as the toxicity of the HE-02. In the hemolysis experiment, HE-02 inducted only 5,01% of hemolysis on the higher concentration tested (1000ug/mL), suggesting low cytotoxicity in mouse erythrocytes. In RAW 264.7 cell lines, HE-02 inducted 49,75% of cytotoxicity after treatment with 1000ug/mL. In the pre-clinical test of toxicity, the 50% lethal dose (LD50) was estimated around 2000 mg/kg, which allowed the choice of safe doses to be used in the pharmacological test. In the Ehrlich ascites tumor model, HE-02 (12,5 or 25 mg/kg) showed antitumor activity by reducing viability and total cell parameters (p<0,05), without altering tumor volume and mass. In the analysis of the cell cycle profile, HE-02 (12,5 mg/kg) induced a small increase of only 10% in the sub-G1 peak (p<0,05) in relation to the control, suggesting that alterations in the cell cycle do not represent an important mechanism in the antitumor effect of HE-02. The treatment with HE-02 (12,5 mg/kg) reduced the peritumoral vascular microdensity (p<0,05), indicating antiangiogenic action. Regarding the evaluation of cytokines of the tumor microenvironment, it was observed that HE-02 increased the concentrations of IL-1β, TNF-α and IL-12, while reducing IL-4 and IL-10 cytokines (p<0,05 for all). In addition, HE-02 induced the increase of concentrations of reactive oxygen species (ROS) and nitric oxide (NO) in the peritoneal fluid (p<0,05). These data together suggest that HE-02 promotes modulation of the immune system in the sense of stimulating a profile of T helper lymphocyte 1 (Th1), which is cytotoxic to tumor cells. Regarding the evaluation of toxicity in the Ehrlich carcinoma model, a reduction in body weight was observed in addition to an increase in urea, but kidney damage was ruled out by histological analysis of the kidneys. Furthermore, leukocytosis was observed, accompanied by neutrophilia and lymphopenia. These results suggest that HE-02 shows low toxicity and antitumor activity in vivo by stimulation of the immune system.