Abstract
This study aimed to evaluate the intestinal mucosa of the duodenum and jejunum of Walker-256 tumor-bearing rats supplemented with l-glutamine. Thirty-two male 50-day-old Wistar rats (Rattus norvegicus) were randomly divided into four groups: control (C), control supplemented with 2 % l-glutamine (GC), Walker-256 tumor (WT), and Walker-256 tumor supplemented with 2 % l-glutamine (TWG). Walker-256 tumor was induced by inoculation viable tumor cells in the right rear flank. After 10 days, celiotomy was performed and duodenal and jejunal tissues were removed and processed. We evaluated the cachexia index, proliferation index, villus height, crypt depth, total height of the intestinal wall, and number of goblet cells by the technique of periodic acid-Schiff (PAS). Induction of Walker-256 tumor promoted a reduction of metaphase index in the TW group animals, which was accompanied by a reduction in the villous height and crypt depths, resulting in atrophy of the intestinal wall as well as increased PAS-positive goblet cells. Supplementation with l-glutamine reduced the tumor growth and inhibited the development of the cachectic syndrome in animals of the TWG group. Furthermore, amino acid supplementation promoted beneficial effects on the intestinal mucosa in the TWG animals through restoration of the number of PAS-positive goblet cells. Therefore, supplementation with 2 % l-glutamine exhibited a promising role in the prevention of tumor growth and cancer-associated cachexia as well as restoring the intestinal mucosa in the duodenum and jejunum of Walker-256 tumor-bearing rats.
Similar content being viewed by others
References
Abrahão SAB, Machado EC (2014) Suplementação de Glutamina no Tratamento de Pacientes com Câncer: uma revisão bibliográfica. Estudos 41(2):215–222
Alves EPB, Alves AMP, Pereira RVF, Neto MHdM, Zanoni JN (2010) Immunohistochemical study of vasoactive intestinal peptide (VIP) enteric neurons in diabetic rats supplemented with l-glutamine. Nutr Neurosci 13(1):43–51
Araki Y, Mukaisyo K-I, Sugihara H, Fujiyama Y, Hattori T (2010) Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. Oncol Rep 24(4):869–874
Barton BE (2001) IL-6-like cytokines and cancer cachexia. Immunol Res 23(1):41–58
Beamish RJ (1972) Lethal pH for the white sucker Catostomus commersoni (Lacepede). Trans Am Fish Soc 101(2):355–358
Braga C, Silva A, Sant’Ana D, Araújo E (2011) Infecção toxoplásmica causa hipertrofia da parede do cólon de frangos. Arq bras med vet zootec 63(2):340–347
de Morais H, Cassola P, Moreira CCL, Bôas SKFV, Borba-Murad GR, Bazotte RB, de Souza HM (2012) Decreased response to cAMP in the glucose and glycogen catabolism in perfused livers of Walker-256 tumor-bearing rats. Mol Cell Biochem 368(1–2):9–16
Diestel CF, Marques RG, Lopes-Paulo F, Paiva DD, Horst NL, Caetano CER, Portela MC (2007) l-Glutamine supplementation optimizes the repair of the colonic mucosa in rats subjected to abdominal irradiation. Nutr Res 27(10):647–652
Fillmann H, Kretzmann NA, San-Miguel B, Llesuy S, Marroni N, González-Gallego J, Tuñón MJ (2007) Glutamine inhibits over-expression of pro-inflammatory genes and down-regulates the nuclear factor kappaB pathway in an experimental model of colitis in the rat. Toxicology 236(3):217–226
Fracaro L, Frez FCV, Silva BC, Vicentini GE, Souza SRG, Martins HA, Linden DR, Guarnier FA, Zanoni JN (2016) Walker 256 tumor-bearing rats demonstrate altered interstitial cells of Cajal. Effects on ICC in the Walker 256 tumor model. Neurogastroenterol Motil 28(1):101–115
Guarnier FA, Cecchini AL, Suzukawa AA, Maragno ALG, Simão AN, Gomes MD, Cecchini R (2010) Time course of skeletal muscle loss and oxidative stress in rats with Walker 256 solid tumor. Muscle Nerve 42(6):950–958
Hermes-Uliana C, Panizzon CPdNB, Trevizan AR, Sehaber CC, Ramalho FV, Martins HA, Zanoni JN (2014) Is l-glutathione more effective than l-glutamine in preventing enteric diabetic neuropathy? Dig Dis Sci 59(5):937–948
Hu K, Feng L, Jiang W, Liu Y, Jiang J, Li S, Zhou X (2014) Oxidative damage repair by glutamine in fish enterocytes. Fish Physiol Biochem 40(5):1437–1445
Kuhn KS, Muscaritoli M, Wischmeyer P, Stehle P (2010) Glutamine as indispensable nutrient in oncology: experimental and clinical evidence. Eur J Nutr 49(4):197–210
Lelbach A, Muzes G, Feher J (2007) Current perspectives of catabolic mediators of cancer cachexia. Med Sci Monit 13(9):RA168–RA173
Lima MMR, de Mello MAR, Curi R (2002) Walker 256 tumour growth causes marked changes of glutamine metabolism in rat small intestine. Cell Biochem Funct 20(2):107–113
Lira FSd, Yamashita AS, Rosa J, Koyama C, Caperuto E, Batista M Jr, Seelaender MCL (2012) Exercise training decreases adipose tissue inflammation in cachectic rats. Horm Metab Res 44(2):91
Liu S-L, Shi D-Y, Shen Z-H, Wu Y-D (2000) Effects of glutamine on tumor growth and apoptosis of hepatoma cells. Acta Pharmacol Sin 21(7):668–672
Loberg RD, Bradley DA, Tomlins SA, Chinnaiyan AM, Pienta KJ (2007) The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA Cancer J Clin 57(4):225–241
Matés JM, Pérez-Gómez C, de Castro IN, Asenjo M, Márquez J (2002) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34(5):439–458
Miksza DR, de Souza CO, de Morais H, da Rocha AF, Borba-Murad GR, Bazotte RB, de Souza HM (2013) Effect of infliximab on metabolic disorders induced by Walker-256 tumor in rats. Pharmacol Rep 65(4):960–969
Mithieux G, Rajas F, Gautier-Stein A (2004) A novel role for glucose 6-phosphatase in the small intestine in the control of glucose homeostasis. J Biol Chem 279(43):44231–44234
Myers RB, Fredenburgh JL, Grizzle WE (2008) Carbohydrates. In: Jones ML, Bancroft JD, Gamble M (eds) Theory and practice of histological techniques, 6th edn. Elsevier, China, pp 161–187
Newsholme P, Lima M, Procopio J, Pithon-Curi T, Bazotte R, Curi R (2003a) Glutamine and glutamate as vital metabolites. Braz J Med Biol Res 36(2):153–163
Newsholme P, Procopio J, Lima MMR, Pithon-Curi TC, Curi R (2003b) Glutamine and glutamate—their central role in cell metabolism and function. Cell Biochem Funct 21(1):1–9
Noé JE (2009) l-Glutamine use in the treatment and prevention of mucositis and cachexia: a naturopathic perspective. Integr Cancer Ther 8(4):409–415
Papaconstantinou HT, Chung DH, Zhang W, Ansari NH, Hellmich MR, Townsend CM Jr, Ko TC (2000) Prevention of mucosal atrophy: role of glutamine and caspases in apoptosis in intestinal epithelial cells. J Gastrointest Surg 4(4):416–423
Pelicano ERL, Souza P, Souza H, Oba A, Norkus EA, Kodawara LM, Lima T (2003) Morfometria e ultra-estrutura da mucosa intestinal de frangos de corte alimentados com dietas contendo diferentes probióticos. Revista Portuguesa de Ciências Veterinárias 98(547):124–134
Rajas F, Jourdan-Pineau H, Stefanutti A, Mrad EA, Iynedjian PB, Mithieux G (2007) Immunocytochemical localization of glucose 6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase in gluconeogenic tissues reveals unsuspected metabolic zonation. Histochem Cell Biol 127(5):555–565
Roth E (2008) Nonnutritive effects of glutamine. J Nutr 138(10):2025S–2031S
Santos ALBd, Novaes MRCG, Toledo DCd, Cavalcante PHL (2010) Efeitos da Glutamina no Câncer Colorretal Evidências da Literatura. Arquivos de Medicina 24(5):199–205
Takechi H, Mawatari K, Harada N, Nakaya Y, Asakura M, Aihara M, Takizawa H, Goto M, Nishino T, Minato T (2014) Glutamine protects the small intestinal mucosa in anticancer drug-induced rat enteritis model. J Med Invest 61(1–2):59–64
Tashima CM, Tronchini EA, Pereira RVF, Bazotte RB, Zanoni JN (2007) Diabetic rats supplemented with l-glutamine: a study of immunoreactive myosin-V myenteric neurons and the proximal colonic mucosa. Dig Dis Sci 52(5):1233–1241
Tisdale MJ (1999) Wasting in cancer. J Nutr 129(1):243S–246S
Tisdale MJ (2000) Metabolic abnormalities in cachexia and anorexia. Nutrition 16(10):1013–1014
Tisdale MJ (2001) Cancer anorexia and cachexia. Nutrition 17(5):438–442
Tisdale MJ (2002a) Cachexia in cancer patients. Nat Rev Cancer 2(11):862–871
Tisdale MJ (2002b) Pathogenesis of cancer cachexia. J Support Oncol 1(3):159–168
Tisdale MJ (2004) Tumor–host interactions. J Cell Biochem 93(5):871–877
van Zanten AR (2015) Glutamine and antioxidants: status of their use in critical illness. Curr Opin Clin Nutr Metab Care 18(2):179–186
Watford M, Tatro AV (1989) Phosphoenolpyruvate carboxykinase of rat small intestine: distribution and regulation of activity and mRNA levels. J Nutr 119(2):268–272
Zucoloto S, Diaz J, Oliveira J, Muccilo G, Sales Neto V, Kajiwara J (1988) Effect of chemical ablation of myenteric neurones on intestinal cell proliferation. Cell Prolif 21(4):213–219
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
Fundação Araucária/266/2014.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Handling Editor: G. J. Peters.
Rights and permissions
About this article
Cite this article
Martins, H.A., Sehaber, C.C., Hermes-Uliana, C. et al. Supplementation with l-glutamine prevents tumor growth and cancer-induced cachexia as well as restores cell proliferation of intestinal mucosa of Walker-256 tumor-bearing rats. Amino Acids 48, 2773–2784 (2016). https://doi.org/10.1007/s00726-016-2313-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-016-2313-1