Abstract
The essential oil from Croton polyandrus Spreng., Euphorbiaceae, leaves was tested for the toxicity and antitumor activity. The concentration producing 50% hemolysis was 141 μg/ml on mice erythrocytes. In the acute toxicological study, the estimated LD50 was 447.18 mg/kg. The essential oil did not induce increase in number of micronucleated erythrocytes, suggesting low genotoxicity. Essential oil (100 or 150 mg/kg) showed significant antitumor activity in Ehrlich ascitic carcinoma model. We observed that essential oil induces cell-cycle arrest at the G0/G1 phase, and increases the sub-G1 peak, which represents a marker of cell death by apoptosis. Survival also increased for the treated animals. The toxicological analyses revealed reduction in body weight, increased aspartate aminotransferase and alanine aminotransferase activity, hematological changes, and a thymus index reduction. These data suggest gastrointestinal and liver toxicity, anemia, leukopenia/lymphocytopenia, and immunosuppressive effects. Histopathological analysis revealed the weak hepatotoxicity of essential oil. In summary, essential oil of C. polyandrus displays in vivo antitumor activity and moderate toxicity.
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Almeida, R.N., Navarro, D.S., Barbosa-Filho, J.M., 2001. Plants with central analgesic activity. Phytomedicine 8, 310–322.
Amelo, W., Nagpal, P., Makonnen, E., 2014. Antiplasmodial activity of solvent fractions of methanolic root extract of Dodonaea angustifolia in Plasmodium berghei infected mice. BMC Complement. Altern. Med. 14, 462–468.
Anvisa, 2013. Determina a publicação do Guia para a condução de estudos não clínicos de toxicologia e segurança farmacológica necessários ao desenvolvimento de medicamentos. Ministério da Saúde. Agência Nacional de Vigilância Sanitária. Diário Oficial da União, Poder Executivo, Brasília, D.F., β1 January 2013.
Araújo, M.J.A.M., Dutra, R.P., Costa, G.C., Reis, A.S., Assunção, A.K.M., Libério, S.A., Maciel, M.C.G., Silva, L.A., Guerra, R.N.M., Ribeiro, M.N.S., Nascimento, F.R.F., 2009. Effect of propolis of Scaptotrigona aff. postica on the development of the tumor of Ehrlich in mice. Rev. Bras. Farmacogn. 20, 580–587.
Bezerra, D.P., Marinho Filho, J.D., Alves, A.P.N.N., Pessoa, C., De Moraes, M.O., Pessoa, O.D.L., Torres, M.C.M., Silveira, E.R., Viana, F.A., Costa-Lotufo, L.V., 2009. Anti-tumor activity of the essential oil from the leaves of Croton regelianus and its component ascaridole. Chem. Biodivers. 6, 1224–1231.
Bhalla, Y., Gupta, V.K., Jaitak, V., 2013. Anticancer activity of essential oils: a review. J. Sci. Food Agric. 93, 3643–3653.
Boussios, S., Pentheroudakis, G., Katsanos, K., Pavlidis, N., 2012. Systemic treatment-induced gastrointestinal toxicity: incidence, clinical presentation and management. Ann. Gastroenterol. 25, 106–118.
Carol, A., 1995. Acute, sub chronic and chronic toxicology. In: CRC (Ed.), Handbook of Toxicology. CRC Press Inc., U.S., pp. 51–104.
Carlini, E.A., 2003. Plants and the central nervous system. Pharmacol. Biochem. Behav. 75, 501–512.
Chen, L., Watkins, J.F., 1970. Evidence against the presence of H2 his to compatibility antigens in Ehrlich ascites tumour cells. Nature 225, 734–735.
Correa-Royero, J., Tangarife, V., Durán, C., Stashenko, E., Mesa-Arango, A., 2009. In vitro antifungal activity and cytotoxic effect of essential oils and extracts of medicinal and aromatic plants against Candida krusei and Aspergillus fumigatus. Rev. Bras. Farmacogn. 20, 734–741.
Cragg, G.M., Newman, D.J., 2013. Natural products: a continuing source of novel drug leads. Biochim. Biophys. Acta 1830, 3670–3695.
Darzynkiewicz, Z., Bruno, S., Del Bino, B.G., Gorczyca, W., Hotz, M.A., Lassota, P., Traganos, F., 1992. Features of apoptotic cells measured by flow cytometry. Cytometry 13, 795–808.
Dolai, N., Karmakar, I., Kumar, R.B.S., Kar, B., Bala, A., Haldar, P.K., 2012. Evaluation of antitumor activity and in vivo antioxidant status of Anthocephalus cadamba on Ehrlich ascites carcinoma treated mice. J. Ethnopharmacol. 142, 865–870.
El-Sayyad, H.I., Ismail, M.F., Shalaby, F.M., Abou-El-Magd, R.F., Rajiv, L.G., Augusta, F., Madhwa, H.G.R., Allal, O., 2009. Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int. J. Biol. Sci. 5, 466–473.
Fernandes, H.M.B., Oliveira-Filho, A.A., Sousa, J.P., Oliveira, T.L., Lima, E.O., Meireles, D.R., Brito, M.T., Zelioli, I.A.M., Queiroz, N.C.A., Foglio, M.A., Ruiz, A.L.T.G., Carvalho, J.E., Silva, M.S., Castello-Branco, M.V.S., Tavares, J.F., 2012. Antitumor, antimicrobial effect and chemical composition of the essential oil of Croton polyandrus Spreng. Lat. Am.J. Pharm. 31, 1430–1434.
Fernandes, H.M.B., Leão, A.D., Oliveira-Filho, A.A., Sousa, J.P., Oliveira, T.L., Lima, E.O., Silva, M.S., Tavares, J.F., 2013. Antimicrobial activity and phytochemical screeningofextracts from leaves of Croton polyandrus Spreng. Int.J. Pharmacogn. Phytochem. Res. 5, 223–226.
Gad, S.C., 2007. Animal Models in Toxicology. Taylor & Francis, ISBN 0824754077.
Gaspar, B.L., Sharma, P., Das, R., 2015. Anemia in malignancies: pathogenetic and diagnostic considerations. Hematology 1, 18–25.
Gordon, H., Sweet, H.H., 1936. A simple method forthe silver impregnation of reticulin.Am.J. Pathol. 12, 545–551.
Gould, M.N., 1997. Cancer chemoprevention and the rapyby monoterpenes. Environ. Health Perspect. 105, 977–979.
Grinberg, L.N., Newmark, H., Kitrossky, N., Rahamim, E., Chevion, M., Rachmilewitz, E.A., 1997. Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem. Pharmacol. 54, 973–978.
Hanahan, D., 2014. Rethinking the war on cancer. Lancet 383, 558–563.
Jain, D., Pathak, N., Khan, S., Raghuram, G.V., Bhargava, A., Samarth, R., Mishra, P.K., 2011. Evaluation of cytotoxicity and anticarcinogenic potential of Mentha leaf extracts. Intern. J. Toxicol. 30, 225–236.
Kang, C., Munawir, A., Cha, M., 2009. Cytotoxicity and hemolytic activity of jellyfish Nemopilema nomurai (Scyphozoa: Rhizostomeae) venom. Comp. Biochem. Physiol. 150, 85–90.
Kiang, J.G., Smith, J.T., Agravante, N.G., 2009. Geldanamycin analog 17-DMAG inhibits iNOSand caspases ingamma-irradiated humanT cells. Radiat. Res. 172, 321–330.
Kin, J.H., Lee, S.J., Han, Y.B., 1994. Isolation of isoguanosine from Croton tiglium and its antitumor activity. Arch. Pharmacol. Res. 17, 115–118.
Lins, K.O., Bezerra, D.P., Alves, A.P.N.N., Alencar, N.M., Lima, M.W., Torres, V.M., Farias, W.R., Pessoa, C., de Moraes, M.O., Costa-Lotufo, L.V., 2009. Antitumor properties of a sulfated polysaccharide from the red seaweed Champia feldmannii (DiazPifferer). J. Appl. Toxicol. 29, 20–26.
Liu, W., Zhang, C.C., Li, K., 2013. Prognostic value of chemotherapy-induced leukopenia in small-cell lung cancer. Cancer Biol. Med. 10, 92–98.
Lopes, D., Bizzo, H.R., Sobrinho, A.F.S., Pereira, M.V.G., 2003. Essential oil from leaves of Croton sacaquinha Benth. J. Essent. Oil Res. 15, 48–49.
Maroni, L.C., Silveira, A.C.O., Leite, E.A., Melo, M.M., Ribeiro, A.F.C., Cassali, G.D., Souza, C.M., Fagundes, E.M.S., Caldas, I.R., Araújo, M.S.S., et al., 2012. Antitumor effectiveness and toxicity of cisplatin-loaded long-circulating and pH-sensitive liposomes against Ehrlich ascitic tumor. Exp. Biol. Med. 237, 973–984.
Montenegro, R.C., Farias, R.A.F., Pereira, M.R.P., Alves, A.P.N.N., Bezerra, F.S., Neto, M.A., Pessoa, C., Moraes, M.O., Costa-Lotufo, L.V., 2008. Antitumor activity of pisosterol in mice bearing withS180 tumor. Biol. Pharm. Bull. 31, 454–457.
Nascimento, F.R.F., Cruz, G.V.B., Pereira, P.V.S., 2006. Ascitic and solid Ehrlich tumor inhibition by Chenopodium ambrosioides L. treatment. Life Sci. 78, 2650–2653.
Ng, T.B., Li, W.W., Yeung, H.W., 1986. A steryl glycoside fraction with hemolytic activity from tubers of Momordica cochinchinensis. J. Ethnopharmacol. 18, 5–6.
Nissenson, A.R., Goodnough, L.T., Dubois, R.W., 2003. Anemia. Not just an innocent bystander? Arch. Intern. Med. 163, 1400–1404.
OECD (The Organisation for Economic Co-operation and Development), 1997. Mammalian Erythrocyte Micronucleus Test: Guidelines for Testing of Chemicals. nc 474.
Oliveira, A.C., Leal-Cardoso, J.H., Santos, C.F., Morais, S.M., Coelho, A.N.S., 2001. Antinociceptive effects of the essential oil of Croton zehntneri in mice. Braz. J. Med. Biol. Res. 34, 1471–1474.
Ozaslan, M., Karagoz, I.D., Kilic, I.H., Guldur, M.E., 2011. Ehrlich ascites carcinoma. Afr. J. Biotechnol. 10, 2375–2378.
Pereira, A.S., Carbonell, A.S., Aquino Neto, F.R., Amaral, A.C.F., Barnes, R.A., 2002. High-temperature gas chromatography-mass spectrometry with glass capillary columns for the screening of natural products. J. Chromatogr. A 947, 255–265.
Rasmussen, L., Arvin, A., 1982. Chemotherapy-induced immunosuppression. Environ. Health Perspect. 43, 21–25.
Rodrigues, K.A.F., Amorim, L.V., Oliveira, J.M.G., 2013. Eugenia uniflora L. essential oil as a potential anti-Leishmania agent: effects on Leishmania amazonensis and possible mechanisms of aqction. Evid. Based Complement. Altern. Med., https://doi.org/10.1155/2013/279726.
Safarzadeh, E., Shotorbani, S.S., Baradaran, B., 2014. Herbal medicine as inducers of apoptosis in cancer treatment. Adv. Pharm. Bull. 4, 421–427.
Salgado Oloris, S.C., Dagli, M.L.Z., Guerra, J.L., 2002. Effect of h-caroteneon the development of the solid Ehrlichtumor in mice. Life Sci. 71, 717–724.
Shrivastav, S., Stone, K.R., Paulson, D.F., Bonar, R.A., 1980. Activation of cyclophosphamide forin vitro testing of cell sensitivity. Cancer Res. 40, 4443–4445.
Silva, S.L., Chaar, J.S., Figueiredo, P.M.S., Tomomasa, Y., 2008. Cytotoxic evaluation of essential oil from Casearia sylvestris Sw onhuman cancer cells and erythrocytes. Acta Amaz. 38, 107–112.
Sun, Q., Li, R.T., Guo, W., 2006. Novel class of cyclophosphamide prodrug: cyclophosphamide spiropiperaziniums (CPSP). Bioorg. Med. Chem. Lett. 16, 3727–3730.
Sylvestre, M., Pichette, A., Longtin, A., Nagau, F., Legault, J., 2006. Essential oil analysis and anticancer activity of leaf essential oil of Croton flavens L. from Guadeloupe. J. Ethnopharmacol. 103, 99–102.
Torti, V.R., Cobb, A.J., Everitt, J.L., Marshall, M.W., Boorman, G.A., Butterworth, B.E., 2001. Nephrotoxicity and hepatotoxicity induced by inhaled bromodichloromethane in wild-type and p53-heterozygous mice. Toxicol. Sci. 64, 269–280.
Verçosa Júnior, D., Souza-Fagundes, E.M., Cassali, G.D., Ribeiro, E.L., Zani, C.L., Melo, M.M., 2006. Efeito do miriadenolídeo isolado de Alomia myriadenia (Asteraceae) sobre o tumor de Erlichascíticonocamundongo. Arq. Bras. Med. Vet. Zootec. 58, 788–798.
Vieira, P., Santos, S., Chen-Chen, L., 2010. Assessment of mutagenicity and cytotoxicity of Solanum paniculatum L. extracts using in vivo micronucleus test in mice. Braz.J. Biol. 70, 601–606.
Wang, W., Li, N., Luo, M., Yuangang, Z., Efferth, T., 2012. Antibacterial activity and anticancer activity of Rosmarinus officinalis L. essential oil compared to that of its maincomponents. Molecules 17, 2704–2713.
Wu, C.S., Chen, Y.J., Chen, J.J.W., Shieh, J.J., Huang, C.H., Lin, P.S., Chang, G.C., TsaiChang, J.H., Lin, C.C., 2012. Terpinen-4-ol induces apoptosis in human nonsmall cell lung cancer in vitro and in vivo. Evid. Based Complement. Altern. Med., https://doi.org/10.1155/2012/818261.
Zhang, A., Zhu, Q.Y., Luk, Y.S., Ho, K.Y., Fung, K.P., Chen, Z.Y., 1997. Inhibitory effects of jasmine green tea epicatechin isomers on free radical-induced lysis of red blood cells. Life Sci. 61, 383–394.
Zheng, G.Q., Kenney, P.M., Lam, L.K.T., 1992. Sesquiterpenes from clove (Eugenia caryophyllata) as potential anticarcinogenic agentes. J. Nat. Prod. 55, 999–1003.
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DRPM, HMBF, TLR, TMB, VMM, TKGS, JCLRP, ALX, DMB, MVS participated in study concept and design, acquisition of data, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content. JFT and MSS carried out the extraction of essential oil and participated in drafting the manuscript. KKPM performed the histopathological analysis.
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Meireles, D.R.P., Fernandes, H.M.B., Rolim, T.L. et al. Toxicity and antitumor efficacy of Croton polyandrus oil against Ehrlich ascites carcinoma cells. Rev. Bras. Farmacogn. 26, 751–758 (2016). https://doi.org/10.1016/j.bjp.2016.05.014
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DOI: https://doi.org/10.1016/j.bjp.2016.05.014