Cancer is the given name for a group of more than 100 diseases account for 13% of deaths worldwide and 15.1% in Brazil, with estimates of increased mortality. These data show the deficiency of more effective anticancer agents, leading to increased life expectancy or cure. In this context, nature is an alternative to the problem, for harboring a huge biodiversity and Brazil stands out for having the highest diversity of plant species in the world, but little explored as their biological characteristics. The genus Mentha has its very widespread species in the country, with many evidenced therapeutic activities, among them the potential anticancer action of essential oil (EO) demonstrated in two species (Mentha piperita e Mentha spicata). However, this study aimed to evaluate the antitumor activity of the essential oil of Mentha x villosa Hudson (OEMV) in vitro and in vivo, and its toxicity in vivo. For this, the EO was extracted from the leaves of Mentha x villosa, 12 of its constituents have been identified and their main constituent, the monoterpene rotundifolone was isolated. The in vitro cytotoxicity of OEMV rotundifolone and 3 were evaluated against tumor cell lines: ovarian adenocarcinoma (OVACAR-8), colon carcinoma (HCT-116) and glioblastoma (SF295) by the MTT assay. The OEMV showed cytotoxic activity in all cell lines tested, with IC50 ranging from 0.57 to 1.02 ìg/mL. However, rotundifolone did not show cytotoxicity at the tested concentrations, suggesting that the activity of the oil is not mediated by its major constituent. Considering this result, we evaluated the antitumor activity of OEMV in vivo using mice transplanted with sarcoma 180. In this study, it was showed antitumor activity in OEMV treatments performed by intraperitoneal (32.02 and 42.81% with 50 and 100 mg/kg/day, respectively) and orally (34.27 and 43.22% with 100 and 200 mg/kg/day, respectively), probably due to synergy among its constituents. No change was observed in the toxicological parameters evaluated in animals treated with OEMV: variation in body mass, organ weights (liver, spleen and kidney), blood biochemical parameters (AST, ALT, urea and creatinine) and ulcerative lesion index (this later only in the groups treated orally). Since the results demonstrated that OEMV has antitumor activity with low toxicity, it was proposed to evaluate the benefit of the association between OEMV (50 and 100 mg/kg/day) and 5-fluorouracil (5-FU, 10 mg/kg/day) reference known antineoplasic and toxicity. The association promoted tumor growth inhibition of 50.3% and 65.2% at doses of 50 and 100 mg/kg/day, respectively. The highest dose of OEMV in combination showed the same statistical difference that the level of inhibition of 5-FU at the highest dose (25 mg/kg/day). The toxicological parameters, variation of body mass and biochemical parameters (AST and ALT) showed alterations similar as the positive control. The organ weight alterations did not occur, a result that demonstrates an evident benefit of the combination compared to the group treated with 5-FU alone. The last toxicological endpoints evaluated were hematological parameters where both groups showed changes associated with differential count (lymphocytosis and neutropenia) and reduction in total leukocytes; positive factor in this result is that the reduction was not as intense as the one displayed by the control 5-FU furthermore possibly resulting in a decreased susceptibility to infection. The association promoted tumor growth inhibition 50.3% and 65.2% at doses of 50 and 100 mg/kg/day, respectively. The highest dose of OEMV in combination showed the same statistical difference that the level of inhibition of 5-FU dose (25 mg/kg/day) the toxicological parameters, variation of body mass and biochemical analysis (AST and ALT) showed alterations similar to the positive control. / O cancer e o nome dado a um conjunto de mais de 100 doencas, responsaveis por 13% das mortes no mundo e 15,1% no Brasil, com estimativas de mortalidade crescente. Esses dados refletem a carencia por agentes antineoplasicos mais efetivos, que levem ao aumento da expectativa de vida ou a cura. Nesse contexto, a natureza e uma alternativa para o problema, por abrigar uma gigantesca biodiversidade e o Brasil se destaca, por possuir a maior diversidade de especies de plantas do mundo, mas pouco exploradas quanto suas caracteristicas biologicas. O genero Mentha tem suas especies bem difundidas no pais, com diversas atividades terapeuticas comprovadas, dentre elas o potencial acao anticancer do oleo essencial (OE) comprovadas em duas especies (Mentha piperita e Mentha spicata). Portanto, o presente estudo teve como objetivo avaliar a atividade antitumoral do oleo essencial da Mentha x villosa Hudson (OEMV) in vitro e in vivo, e sua toxicidade in vivo. Para isso, o OE foi extraido a partir das folhas da Mentha x villosa, onde 12 dos seus constituintes foram identificados e isolado seu constituinte majoritario, a rotundifolona . A citotoxicidade in vitro do OEMV e da rotundifolona foi avaliada frente a 3 linhagens de celulas tumorais: adenocarcinoma ovariano (OVACAR-8), carcinoma de colon (HCT-116) e glioblastoma (SF295) atraves do ensaio do MTT. O OEMV apresentou atividade citotoxica em todas as linhagens de celulas testadas, com CI50 variando entre 0,57 e 1,02 Êg/mL. Porem, a rotundifolona nao demonstrou atividade citotoxica nas concentracoes testadas, sugerindo que a atividade do oleo nao e mediada por seu constituinte majoritario. Diante desse resultado, foi avaliada a atividade antitumoral do OEMV in vivo utilizando camundongos transplantados com sarcoma 180. Neste ensaio, o OEMV apresentou atividade antitumoral nos tratamentos realizados pela via intraperitoneal (32,02 e 42,81% com 50 e 100 mg/kg/dia, respectivamente) e pela via oral (34,27 e 43,22% com 100 e 200 mg/kg/dia, respectivamente), por provavel sinergismo entre seus constituintes. Nao foi observada nenhuma alteracao nos parametros toxicologicos avaliados em animais tratados com o OEMV: variacao de massa corporea, massa dos orgaos (figado, baco e rins), analises bioquimicas (AST, ALT, ureia e creatinina) e indice de lesao ulcerativa (este ultimo apenas nos grupos tratados por via oral). Como os resultados demonstraram que o OEMV possui atividade antitumoral, com baixa toxicidade, foi proposto avaliar o beneficio da associacao, via i.p, entre o OEMV (50 e 100 mg/kg/dia) e o 5-Fluorouracil em menor dose (5-FU, 10 mg/kg/dia), antineoplasico de referencia e conhecida toxicidade. A associacao promoveu a inibicao do crescimento tumoral de 50,3% e 65,2% nas doses de 50 e 100 mg/kg/dia, respectivamente. A maior dose do OEMV em associacao demonstrou a mesma diferenca estatistica que o indice de inibicao do 5-FU na maior dose (25 mg/kg/dia). Os parametros toxicologicos, variacao de massa corporea e analise bioquimica (AST e ALT) apresentaram alteracoes semelhantes as do controle positivo. Na massa dos orgaos nao ocorreu alteracao, resultado que demonstra um evidente beneficio da associacao quando comparada ao grupo tratado com 5-FU isolado. O ultimo parametro toxicologico avaliado foram as analises hematologicas onde ambos os grupos associados demonstraram alteracoes na contagem diferencial e reducao na contagem de leucocitos totais; o fator positivo nesse resultado e que a reducao nao foi tao intensa quanto a apresentada pelo controle positivo 5-FU, provocando possivelmente, uma menor susceptibilidade a infeccoes. Diante dos resultados, podemos afirmar que o OEMV tem atividade antitumoral in vitro e in vivo com baixa toxicidade, e que a associacao entre 5-FU e o OEMV potencializa a atividade antitumoral do antineoplasico, diminuindo alguns dos seus efeitos toxicos.
| Identifer | oai:union.ndltd.org:IBICT/oai:ri.ufs.br:riufs/3969 |
| Date | 26 February 2014 |
| Creators | Amaral, Ricardo Guimarães |
| Contributors | Thomazzi, Sara Maria |
| Publisher | Pós-Graduação em Ciências Fisiológicas |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Repositório Institucional da UFS, instname:Universidade Federal de Sergipe, instacron:UFS |
| Rights | info:eu-repo/semantics/openAccess |
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