RESUMO
PURPOSE: (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a phenstatin analog compound. PHT is a known tubulin inhibitor that has potent cytotoxic activity. In the present study, PHT was synthesized and its antitumor activity was determined using in vitro and in vivo experimental models. METHODS: The in vitro cytotoxic activity of the PHT was determined by the MTT assay. The antimitotic and hemolytic effects were determined based on the inhibition of sea urchin embryo development and lysis of mouse erythrocytes, respectively. In vivo antitumor activity was assessed in mice inoculated with sarcoma 180 cells. RESULTS: In vitro, PHT displayed cytotoxicity in tumor cell lines, showing IC(50) values in the nanomolar range. In addition, it inhibited sea urchin embryo development during all phases examined, first and third cleavage and blastula stage. However, PHT did not induce hemolysis using mouse erythrocytes, suggesting that the cytotoxicity of PHT does not involve membrane damage. The in vivo study demonstrated tumor inhibition rates of 30.9 and 48.2% for PHT at doses of 20 and 40 mg/kg, respectively. In addition, PHT was also able to increase the response elicited by 5-fluorouracil (5-FU) from 33.3 to 55.7%. The histopathological analysis of liver, kidney, and spleen showed that they were just moderately affected by PHT treatment. Neither enzymatic activity of transaminases nor urea levels were significantly affected. Hematological analysis showed leukopenia after 5-FU treatment, but this effect was prevented when 5-FU was combined with PHT. CONCLUSIONS: In conclusion, PHT exhibited in vitro and in vivo antitumor effects without substantial toxicity.
Assuntos
Antineoplásicos/farmacologia , Benzofenonas/farmacologia , Crescimento Celular/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise , Moduladores de Tubulina/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/toxicidade , Antimitóticos , Benzofenonas/toxicidade , Linhagem Celular Tumoral , Fluoruracila/farmacologia , Fluoruracila/toxicidade , Células HL-60 , Humanos , Masculino , Camundongos , Ouriços-do-Mar/embriologia , Moduladores de Tubulina/toxicidadeRESUMO
The agglutinin from the red marine alga Hypnea cervicornis (HCA) was tested in models of nociception and inflammation. The role of carbohydrate-binding sites and the systemic toxicity were assessed. HCA (10(-1), 1, and 10 mg/kg) administered i.v. to mice inhibited writhes induced by acetic acid and, at 10 mg/kg, inhibited the second phase of the formalin test, but did not alter the response latency in the hot-plate test. HCA (1 mg/kg) administered i.v. to rats reduced carrageenan-induced paw edema at 1, 2, and 3 h after challenge, but not edema induced by dextran. The neutrophil migration induced by both N-formyl-methionyl-leucyl-phenylalanine (fMLP) and carrageenan was inhibited by HCA at 10(-1), 1, and 10 mg/kg. The combination of HCA (1 mg/kg) and its ligand mucin reversed the lectin inhibitory effect on carrageenan-induced neutrophil migration and acetic acid-induced writhes. The i.v. treatment of rats with HCA (1 mg/kg) for 7 days did not affect body mass; liver, kidney or heart wet weight; blood leukocyte counts; urea, creatinine or serum transaminase activity; or macroscopy of the organs examined. In short, H. cervicornis agglutinin showed important antinociceptive and anti-inflammatory activity via interaction with the lectin carbohydrate-binding site.