Associação entre o extrato aquoso e o óleo essencial do Cymbopogon citratus e o 5-fluorouracil na resposta antitumoral em camundongos com sarcoma 180

• Ano de defesa: 2022
• Autor(a) principal: Santana, Ingrede Tatiane Serafim
• Orientador(a): Carvalho, Adriana Andrade
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Programa de Pós-Graduação: Pós-Graduação em Ciências Fisiológicas
• Palavras-chave em Português: Interações ervas-drogas; Plantas medicinais; Capim - santo; Anticarcinógenos; Fluoruracila
• Palavras-chave em Inglês: Herb-drug interactions; Plants, medicinal; Cymbopogon; Anticarcinogenic agents; Fluorouracil
• Área do conhecimento CNPq: CIENCIAS BIOLOGICAS::FISIOLOGIA
• Link de acesso: http://ri.ufs.br/jspui/handle/riufs/16236

In oncology, chemotherapy remains the most prevalent therapy, using antineoplastic drugs such as 5-fluorouracil (5-FU). However, due to limitations, such as cellular non-specificity and associated adverse effects, the use of alternative therapies, such as medicinal plants, has gradually been observed among cancer patients, mainly with the aim of mitigating associated adverse effects, such as nausea and vomiting. The Cymbopogon citratus, popularly known as lemongrass, is among the medicinal plants used by cancer patients; however, despite the identification of beneficial properties in its use, the association of its preparations (such as extracts and essential oils) with antineoplastics is little explored. In this sense, the present study aimed to investigate the association between the aqueous extract and the essential oil of Cymbopogon citratus and 5-fluorouracil in the antitumor response in mice with Sarcoma 180. This is an experimental study approved by the Animal Research Ethics Committee (CEPA), opinions nº 17/2019 and nº 2726280621. Chromatographic analysis was performed to identify constituents of the extract and essential oil of Cymbopogon citratus. In vitro assays were performed to evaluate cytotoxicity in lung cancer (A549), melanoma (B16-F10) and glioma (C6) tumour cell lines, using the Sulforhodamine B method, and to evaluate the presence of hemolytic activity in erythrocytes, through of hemolysis assay. The evaluation of the association of the aqueous extract of Cymbopogon citratus (EACC) and Cymbopogon essential oil citratus (OECC) with 5-FU was performed in an in vivo assay using the experimental tumour Sarcoma 180 in a 9-day protocol (1st day - inoculation of the S180 tumour in the left axillary region; 2nd to 8th day - oral treatments (EACC, OECC and vehicle) or intraperitoneal (5 - FU), and 9th day - a collection of blood material, organs (liver, kidneys and spleen) and tumors); additional analyzes were also carried out with citral, the constituent identified as the majority of the OECC; the doses used corresponded to 50 and 100 mg/kg/day for EACC, 25 and 50 mg/kg/day for OECC and citral and 25 mg/kg/day for 5-FU. The parameters evaluated in relation to the association of EACC, OECC or the isolated citral constituent with 5-FU included tumour inhibition and toxicological aspects related to body mass, water intake and feed consumption, organ mass, renal biochemical parameters (urea, creatinine and uric acid) and liver (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase), erythrocyte hematological parameters (red blood cells, hemoglobin and hematocrit) and leukocytes (total and differential leukocytes) and morphological analysis of the organs. Statistical analyzes included non-linear regression, the Shapiro Wilk normality test, one-way and two-way analysis of variance and Tukey's post-test, using the Prisma program version 8.0.2 (GraphPad Software). The chromatographic analysis identified that chlorogenic acid is present in the EACC and that citral represents the major constituent of the OECC. In vitro assays showed that EACC showed weak cytotoxic activity for A549, B16 - F10 and C6 tumour lines, with a degree of cellular inhibition (GI%) < 50%; in turn, OECC and citral showed high cytotoxic activity for the evaluated strains, with %GI > 75%; additionally, the OECC showed an inhibitory concentration capable of causing 50% of the maximum effect (CI50) < 30 μg / mL for A549 and B16-F10 strains, considered promising for oncology. Hemolysis assay identified that EACC showed low toxicity to erythrocytes at a concentration of 1000 μg / mL; in turn, OECC and citral showed toxicity at concentrations of 500 and 1000 μg / mL and low toxicity at concentrations of 250 μg / mL. An in vivo assay to investigate the association of EACC, OECC and citral with 5-FU, identified that there was no significant influence of the association x in relation to the inhibition of tumour growth of S180. In the experiment with EACC, the treatment of S180 with 5-FU showed tumor growth of 0,36 ± 0,07 g and the treatments with EACC 50 and 100 mg/kg/day + 5 – FU of 0,67 ± 0,08 g (p=0,3532) and 0,57 ± 0,06 (p=0,7539), respectively. In the experiment with OECC and with the isolated citral constituent, group 5 - FU showed tumor growth of 0,22 ± 0,04 g, the groups treated with 25 and 50 mg/kg/day of OECC + 5-FU of 0,55 ± 0,13 g (p=0,3235) and 0,24 ± 0,07 g (p>0,9999) and for citral 25 and 50 mg/kg/day + 5-FU of 0,28 ± 0, 04 g (p=0,9971) and 0,22 ± 0,06 g (p>0, 9999), respectively. Toxicological analyzes identified that the association of EACC with 5-FU resulted in changes in renal biochemical parameters; elevation of uric acid was identified against the association of EACC 100 mg/kg/day with 5-FU and a reduction in creatinine was identified against the association between EACC 50 and 100 mg/kg/day with 5-FU, suggesting that despite the presence of uric acid elevation, a nephroprotective role may be present in reducing creatinine values in relation to the 5-FU treated group alone. In the use of OECC 50 mg/kg/day with 5- FU, an increase in water intake was found when compared to the isolated treatment of 5-FU, with no statistical difference with the negative control with tumour, suggesting the preservation of drinking habits of water altered by 5-FU; no toxicological alterations related to the association of the isolated citral constituent with 5 - FU were identified. Thus, the findings point out that the OECC has a promising role against the B16 - F10 and A549 strains, which may be mainly related to citral, identified as the major constituent of the OECC and which has high cytotoxic activity against the tumour strains evaluated; however, the presence of hemolytic activity in the OECC at concentrations => 250 μg / mL may represent a limitation in its use and should be considered in further analyses. Additionally, the association of EACC, OECC and citral with the antineoplastic 5-FU concluded that there was no influence of the association against tumour inhibition of S180, at the doses used in the present study, and that changes may occur in water intake against the treatment OECC associated with 5 - FU and in renal parameters compared to the associated treatment of EACC with 5 - FU, in oncological therapy.