Avaliação da atividade antitumoral e toxicidade do óleo essencial das folhas de Croton grewioides (Euphorbiaceae).

O câncer pode ser considerado uma doença genética complexa, que resulta de alterações simultâneas em genes geralmente relacionados à proliferação, diferenciação e morte celular. Os produtos naturais são amplamente utilizados no tratamento do câncer. Croton grewioides é conhecida popularmente como “canelinha” ou “canelinha-de-cheiro” e é uma espécie pouco relatada na literatura tanto do ponto de vista farmacológico como toxicológico. O estudo fitoquímico caracterizou o óleo essencial obtido das folhas, que tem como constituinte marjoritário o α-pineno. Este trabalho teve como objetivo avaliar a atividade antitumoral e toxicidade do óleo essencial das folhas de C. grewioides (O.E.C.), através de ensaios in vitro e in vivo. No bioensaio frente A. salina, o valor de CL50 obtido foi 191,4 (185,4 – 197,6) μg/mL. O valor de CH50 obtido no experimento de citotoxicidade em eritrócitos (hemólise) foi 370,3 (357,0 – 384,0) μg/mL. Na avaliação de citotoxicidade em células tumorais Sarcoma 180, através do ensaio de redução do MTT, o O.E.C. mostrou uma inibição do crescimento tumoral, de maneira concentração-dependente, com valor de CI50 de 217,7 (212,6 - 223,0) μg/mL. Durante o ensaio de toxicidade aguda, os animais apresentaram alterações comportamentais depressoras. O valor estimado da DL50 obtido foi 366,1 mg/kg. Na avaliação da atividade antitumoral in vivo frente sarcoma 180, as taxas de inibição do crescimento tumoral foram, 19,3 e 39,7 % após tratamento com 60 e 120 mg/kg do O.E.C., respectivamente, quando comparados ao grupo controle. As análises toxicológicas desses animais mostraram que não houve alteração no índice de baço e timo após os tratamentos, alterações estas que ocorrem com quimioterápicos utilizados na prática clínica, nem dos rins, coração e fígado, quando comparado ao grupo controle transplantado. Portanto, é possível inferir que o O.E.C. não apresentou atividade imunoestimulante como parte do seu mecanismo de ação antitumoral, porém, também não produziu imunossupressão, que representa um dos principais efeitos indesejáveis da maioria dos quimioterápicos utilizados na prática clínica

Toxicity and antitumor potential of Mesosphaerum sidifolium (Lamiaceae) oil and fenchone, its major component

Abstract Background The essential oil from Mesosphaerum sidifolium (L’Hérit.) Harley & J.F.B.Pastore (syn. Hyptis umbrosa), Lamiaceae (EOM), and its major component, have been tested for toxicity and antitumor activity. Methods EOM was obtained from aerial parts of M. sidifolium subjected to hydro distillation, and gas chromatography-mass spectrometry was used to characterize the EOM chemical composition. The toxicity was evaluated using haemolysis assay, and acute toxicity and micronucleus tests. Ehrlich ascites carcinoma model was used to evaluate the in vivo antitumor activity and toxicity of EOM (50, 100 and 150 mg/kg), and fenchone (30 and 60 mg/kg) after 9 d of treatment. Results The EOM major components were fenchone (24.8%), cubebol (6.9%), limonene (5.4%), spathulenol (4.5%), β-caryophyllene (4.6%) and α-cadinol (4.7%). The HC50 (concentration producing 50% haemolysis) was 494.9 μg/mL for EOM and higher than 3000 μg/mL for fenchone. The LD50 for EOM was approximately 500 mg/kg in mice. The essential oil induced increase of micronucleated erythrocytes only at 300 mg/kg, suggesting moderate genotoxicity. EOM (100 or 150 mg/kg) and fenchone (60 mg/kg) reduced all analyzed parameters (tumor volume and mass, and total viable cancer cells). Survival also increased for the treated animals with EOM and fenchone. For EOM 150 mg/kg and 5-FU treatment, most cells were arrested in the G0/G1 phase, whereas for fenchone, cells arrested in the S phase, which represents a blockage in cell cycle progression. Regarding the toxicological evaluation, EOM induced weight loss, but did not induce hematological, biochemical or histological (liver and kidneys) toxicity. Fenchone induced decrease of AST and ALT, suggesting liver damage. Conclusions The data showed EOM caused in vivo cell growth inhibition on Ehrlich ascites carcinoma model by inducing cell cycle arrest, without major changes in the toxicity parameters evaluated. In addition, this activity was associated with the presence of fenchone, its major component

<em>In Vitro </em>and <em>in </em><em>Vivo</em> Antitumor Effect of Trachylobane-360, a Diterpene from<em> Xylopia langsdorffiana</em>

Trachylobane-360 (<em>ent</em>-7α-acetoxytrachyloban-18-oic acid) was isolated from <em>Xylopia langsdorffiana</em>. Studies have shown that it has weak cytotoxic activity against tumor and non-tumor cells. This study investigated the <em>in vitro</em><em> </em>and <em>in vivo</em> antitumor effects of trachylobane-360, as well as its cytotoxicity in mouse erythrocytes. In order to evaluate the <em>in vivo</em> toxicological aspects related to trachylobane-360 administration, hematological, biochemical and histopathological analyses of the treated animals were performed. The compound exhibited a concentration-dependent effect in inducing hemolysis with HC<sub>50</sub> of 273.6 µM, and a moderate <em>in vitro</em><em> </em>concentration-dependent inhibitory effect on the proliferation of sarcoma 180 cells with IC<sub>50</sub> values of 150.8 µM and 150.4 µM, evaluated by the trypan blue exclusion test and MTT reduction assay, respectively. The <em>in vivo</em> inhibition rates of sarcoma 180 tumor development were 45.60, 71.99 and 80.06% at doses of 12.5 and 25 mg/kg of trachylobane-360 and 25 mg/kg of 5-FU, respectively. Biochemical parameters were not altered. Leukopenia was observed after 5-FU treatment, but this effect was not seen with trachylobane-360 treatment. The histopathological analysis of liver and kidney showed that both organs were mildly affected by trachylobane-360 treatment. Trachylobane-360 showed no immunosuppressive effect. In conclusion, these data reinforce the anticancer potential of this natural diterpene