Casearia sylvestris is a plant used in the treatment of several diseases, including cancer. Studies have shown that C. sylvestris presents an interesting antitumoral potential, due to the presence of casearins and some sesquiterpens with antitumoral activity. In this work, we tested the potential chemotherapeutic of two gallic acid-derived compounds isolated from C. sylvestris leaves: isobutyl gallate-3,5-dimethyl ether (IGDE) and methyl gallate-3,5-dimethyl ether (MGDE). We utilized two tumoral models: Ehrlich ascites tumor cells (EAT)/BALB/c mice and Lewis lung cancer cells (LLC1)/C57bl/6 mice. MGDE and IGDE increased the survival of mice inoculated with EAT cells and decreased the tumor volume in the LLC1 model, compared to control groups. Both compounds presented similar and low in vitro cytotoxicity against Ehrlich ascites tumor cells and did not present any significant toxicity against Lewis lung cancer cells. Since the direct in vitro activity against Ehrlich tumor and Lewis lung cancer cells was low, we investigated the effects of MGDE or IGDE treatment on the activity of total natural killer cells from Ehrlich ascites tumor-bearing mice, as a possible explanation for the mechanisms of these compounds in vivo. MGDE and IGDE improved NK cell cytotoxicity against Ehrlich ascites cells. As expected, tumor growth in non-treated mice markedly suppressed NK cell cytolysis while, IGDE completely reversed this effect, when mice were treated with 0.5 mg/kg dosages of these compounds for 4 days. The pharmacokinetic studies showed that IGDE remains in the organism for a long period of time, possibly explaining the higher compound efficiency. © 2009 Elsevier B.V. All rights reserved.6081-37683Alves, T.M.A., Biological screening of Brazilian medicinal plants (2000) Mem. Inst. Oswaldo Cruz, 95, pp. 367-373Barbosa, R.I., Nascimento, S.P., Amorin, P.A.F., Silva, R.F., Notas sobre a composição arbóreo-arbustiva de uma fisionomia das savanas de Roraima, Amazônia Brasileira (2005) Acta Bot. Bras., 19, pp. 323-329Basile, A.C., Sertie, J.A., Panizza, S., Oshiro, T.T., Azzolini, C.A., Pharmacological assay of Casearia sylvestris. 1: Preventive anti-ulcer activity and toxicity of the leaf crude extract (1990) J. Ethnopharmacol., 30, pp. 185-197Chen, P.-N., Chu, S.-C., Chiou, H.-L., Kuo, W.-H., Chiang, C.-L., Hsieh, Y.-S., Mulberry anthocyanins, cyaniding 3-rutinoside and cyaniding 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line (2006) Cancer Lett., 235, pp. 248-259Da Silva, S.L., Figueiredo, P.M.S., Yano, T., Chemotherapeutic potential of the volatile oils from Zanthoxylum rhoifolium Lam leaves (2007) Eur. J. Pharmacol., 576, pp. 180-188Da Silva, S.L., Calgarotto, A.K., Chaar, J., Marangoni, S., Isolation and characterization of ellagic acid derivatives isolated from Casearia sylvestris SW aqueous extract with anti-PLA2 activity (2008) Toxicon, 52, pp. 655-666Da Silva, S.L., Figueiredo, P.M.S., Chaar, J.S., Yano, T., Cytotoxic evaluation of essential oil from Caseria sylvestris on human cancer cells and erythrocytes (2008) Acta Amazon, 38, pp. 107-112Da Silva, S.L., Damico, D.C.S., Figueiredo, P.M.S., Yano, T., Antimicrobial activity of ethanol extract from leaves of Casearia sylvestris (Flacourtiaceae) (2008) Pharm. Biol., 46, pp. 347-351Da Silva, S.L., Calgarotto, A.K., Maso, V., Damico, D.C.S., Baldasso, P.A., Veber, C.L., Villar, J.A.F.P., Marangoni, S., Molecular modeling and inhibition of phospholipase A2 by polyhydroxy phenolic compounds (2009) Eur. J. Med. Chem., 44, pp. 312-321Esteves, I., Souza, I.R., Rodrigues, M., Cardoso, L.G.V., Santos, L.S., Sertie, J.A.A., Perazzo, F.F., Carvalho, J.C.T., Gastric antiulcer and anti-inflammatory activities of the essential oil from Casearia sylvestris Sw (2005) J. Ethnopharmacol., 101, pp. 191-196Hack, C., Longhi, S.J., Boligon, A.A., Murari, A.B., Pauleski, D.T., Análise fitossociológica de uma fragmento de floresta estacional decidual no município de Jaguari, RS (2005) Ciênc. Rural, 35, pp. 1083-1091Hou, J., Sun, T., Hu, J., Chen, S., Cai, X., Zou, G., Chemical composition, cytotoxic and antioxidant activity of the leaf essential oil of Photinia serrulata (2006) Food Chem., 103, pp. 355-358Justo, G.Z., Durán, N., Queiroz, M.L.S., Myelopoietic response in tumor-bearing mice by an aggregated polymer isolated from Aspergillus oryzae (2000) Eur. J. Pharmacol., 388, pp. 219-226Justo, G.Z., Durán, N., Queiroz, M.L.S., Natural killer cell activity, lymphocyte proliferation and cytokine profile in tumor-bearing mice treated with MAPA, a magnesium aggregated polymer from Aspergillus oryzae (2003) Immunopharmacol. Immunotoxicol., 25, pp. 305-319Knapp, D.C., Mata, J.E., Reddy, M.T., Devi, G.R., Iversen, P.L., Resistance to chemotherapeutic drugs overcome by c-Myc inhibition in Lewis lung carcinoma murine model (2003) Anti-Cancer, 14, pp. 39-47Kong, X., Hu, Y., Rui, R., Wang, D., Li, X., Effects of Chinese herbal medicinal ingredients on peripheral lymphocyte proliferation and serum antibody titer after vaccination in chicken (2004) Int. Immunopharmacol., 4, pp. 975-982Lansky, E.P., Newman, R.A., Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer (2007) J. Ethnopharmacol., 109, pp. 177-206Lin, B.-F., Chiang, B.-L., Lin, J.-Y., Amaranthus spinosus water extract directly stimulates proliferation of B lymphocytes in vitro (2005) Int. Immunopharmacol., 5, pp. 711-722Lobo, C., Ruiz-Bellido, M.A., Aledo, J.C., Marquez, J., De Castro, I.N., Alonso, F.J., Inhibition of glutaminase expression by antisense mRNA decreases growth and tumorigenicity of tumor cells (2000) Biochem. J., 348, pp. 257-261Lorenzi, H., Matos, F.J.A., (2002) Plantas Medicinais no Brasil: Nativas e exóticas. Instituto Plantarum de Estudos da Flora LTDA., Nova Odessa, SP, pp. 23-24Maistro, E.L., Carvalho, J.C.T., Mantovani, M.S., Evaluation of the genotoxic potential of the Casearia sylvetris extract on HTC and V79 cells by the comet assay (2004) Toxicol. In vitro, 18, pp. 337-342Mans, D.R.A., Rocha, A.B., Schwartsmann, G., Anti-cancer drug discovery a development in Brazil: targeted plant collection as a rational strategy to acquire candidate anticancer compounds (2000) Oncologist, 2000, pp. 185-198Miller, J.S., The biology of natural killer in cancer, infection, and pregnancy (2001) Exp. Hematol., 29, pp. 1157-1168Mors, W.B., Nascimento, M.C., Pereira, B.M.R., Pereira, N.A., Plant natural products active against snake bite-the molecular approach (2000) Phytochemistry, 55, pp. 627-642Mosaddick, M.A., Banbury, L., Foster, P., Booth, R., Markham, J., Leach, D., Waterman, P.G., Screening of some Australian Flacourtiaceae species for in vitro antioxidant, cytotoxic and antimicrobial activity (2004) Phytomedicine, 11, pp. 461-466Orberlies, N.W., Burgess, J.P., Navarro, H.A., Pinos, R.E., Fairchild, C.R., Petreson, R.W., Soejarto, D.D., Wani, M.E., Novel bioactive clerodane diterpenoids from the leaves and twigs of Casearia sylvestris (2002) J. Nat. Prod., 65, pp. 95-99Raslan, D.S., Jamal, C.M., Duarte, D.S., Borges, M.H., De Lima, M.E., Anti-PLA2 action test of Casearia sylvestris Sw (2002) Boll. Chim. Farm., 141, pp. 457-460Rocci, M.L., Jusko, W.J., LAGRAN program for area and moments in pharmacokinetic analysis (1983) Comput. Programs Biomed., 16, pp. 203-216Ruiz de Morales, J., Velez, D., Subiza, J.L., Ehrlich tumor stimulates extramedullar hematopoiesis in mice without secreting identifiable colony-stimulating factors and without engagement of host T cells (1999) Exp. Hematol., 27, pp. 1757-1767Saleem, A., Husheem, M., Harkonen, P., Pihlaja, K., Inhibition of cancer cell growth by crude extract and phenolics of Terminalia chebul retz. fruit (2002) J. Ethnopharmacol., 81, pp. 327-336Simões, C.M.O., Shenkel, E.P., Gosman, G., Mello, J.C.P., Mentz, L.A., Petrovick, P.R., (2001) Farmacognosia: da planta ao medicamento, pp. 14-39. , UFRGS/UFSC, Florianópolis, SCStorey, B.T., Christian, J.F., Characterization of Lewis lung clonal variants in a model of syngeneic pulmonary murine metastases (2004) Clin. Exp. Metastasis, 21, pp. 265-273Sylvestre, M., Pichette, A., Longtin, A., Nagau, F., Legault, J., Essential oil analysis and anticancer activity of leaf essential oil of Croton flavens L. from Guadeloupe (2006) J. Ethnopharmacol., 103, pp. 99-102Taylor, L., (2002) Herbal Secrets of the Rainforest: Technical data report for guaçatonga, pp. 1-4. , Sage Press, Austin, TXTalmadge, J.E., Singh, R.K., Fidler, I.J., Raz, A., Murine models to evaluate novel and conventional therapeutic strategies for cancer (2007) Am. J. Pathol., 170, pp. 793-804Valadares, M.C., Klein, S.I., Guaraldo, A.M.A., Queiroz, M.L.S., Enhancement of natural killer cell function by titanocenesin mice bearing Ehrlich ascites tumor (2003) Eur. J. Pharmacol., 473, pp. 191-196Veluri, R., Singh, R.P., Liu, Z., Thompson, J.A., Agarwal, R., Agarwal, C., Fractionation of grape seed extract and identification of gallic acid as one of the major active constituents causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells (2006) Carcinogenisis, 27, pp. 1445-1453Xiao, J.B., Chen, X.Q., Zhang, Y.W., Jiang, X.Y., Xu, M., Cytotoxicity of Marchantia convoluta leaf extracts to human liver and lung cancer cells (2006) Braz. J. Med. Biol. Res., 39, pp. 731-738Yamamoto, N., Zou, J.P., Li, X.F., Takenaka, H., Noda, S., Fujii, T., Ono, S., Hamaoka, T., Regulatory mechanisms for production of IFN-g and TNF by antitumor T-cells or macrophages in the tumor-bearing state (1995) J. Immunol., 154, pp. 2281-2290Zhang, Y., Varced, S.K., Nair, M.G., Human tumor cell growth inhibition by nontoxic anthocyanidins, the pigments in fruits and vegetables (2005) Lifes Sci., 76, pp. 1465-1472