Spilanthol, the Principal Alkylamide from Acmella oleracea, Attenuates 5-Fluorouracil-Induced Intestinal Mucositis in Mice

Veronica Santana de Freitas-Blanco; Karin Maia Monteiro; Patrícia Rosa de Oliveira; Ellen Cristina Souza de Oliveira; Lucia Elaine de Oliveira Braga; João Ernesto de Carvalho; Rodney Alexandre Ferreira Rodrigues

doi:10.1055/a-0715-2002

Planta Medica, Table of Contents

Planta Med 2019; 85(03): 203-209
DOI: 10.1055/a-0715-2002

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Spilanthol, the Principal Alkylamide from Acmella oleracea, Attenuates 5-Fluorouracil-Induced Intestinal Mucositis in Mice

Veronica Santana de Freitas-Blanco

¹Pharmacology, Anesthesiology, and Therapeutics, Department of Physiological Sciences, Piracicaba Dental School, University of Campinas, Piracicaba, SP, Brazil

²Chemical, Biological, and Agricultural Pluridisciplinary Research Center (CPQBA), Division of Chemistry of Natural Products, University of Campinas, Paulinia, SP, Brazil

,

Karin Maia Monteiro

³Chemical, Biological, and Agricultural Pluridisciplinary Research Center (CPQBA), Division of Pharmacology and Toxicology, University of Campinas, Paulinia, SP, Brazil

,

Patrícia Rosa de Oliveira

⁴São Paulo State University (UNESP), Department of Biology, Institute of Biosciences, Rio Claro, SP, Brazil

,

Ellen Cristina Souza de Oliveira

³Chemical, Biological, and Agricultural Pluridisciplinary Research Center (CPQBA), Division of Pharmacology and Toxicology, University of Campinas, Paulinia, SP, Brazil

,

Lucia Elaine de Oliveira Braga

¹Pharmacology, Anesthesiology, and Therapeutics, Department of Physiological Sciences, Piracicaba Dental School, University of Campinas, Piracicaba, SP, Brazil

³Chemical, Biological, and Agricultural Pluridisciplinary Research Center (CPQBA), Division of Pharmacology and Toxicology, University of Campinas, Paulinia, SP, Brazil

,

João Ernesto de Carvalho

³Chemical, Biological, and Agricultural Pluridisciplinary Research Center (CPQBA), Division of Pharmacology and Toxicology, University of Campinas, Paulinia, SP, Brazil

⁵Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, SP, Brazil

,

Rodney Alexandre Ferreira Rodrigues

¹Pharmacology, Anesthesiology, and Therapeutics, Department of Physiological Sciences, Piracicaba Dental School, University of Campinas, Piracicaba, SP, Brazil

²Chemical, Biological, and Agricultural Pluridisciplinary Research Center (CPQBA), Division of Chemistry of Natural Products, University of Campinas, Paulinia, SP, Brazil

› Author Affiliations

Abstract

Mucositis is one of the commonest side effects in cancer patients undergoing treatment with radiotherapy and/or chemotherapy, and it currently lacks appropriate and effective treatment. Acmella oleracea, a species of flowering herb from South America, contains spilanthol, an alkylamide that has several pharmacological properties, including anesthetic, analgesic, and anti-inflammatory activities. Therefore, the purpose of this work was to evaluate the effect of spilanthol in intestinal mucositis in Swiss mice induced by 5-fluorouracil (5-FU), an antineoplastic agent administered systemically for the treatment of many different cancers. The repeated administration of 5-FU resulted in intestinal mucositis and consequent decreased food intake, together with weight loss, in all the animals. Daily administration of spilanthol significantly lowered the severity of intestinal mucositis, reducing histopathological changes and increasing the villus height in the animals treated with spilanthol at a dosage of 30 mg/kg (p < 0.0044) compared to a group exposed only to 5-FU. A decrease of myeloperoxidase activity was also observed in the animals treated with 30 mg/kg of spilanthol (p < 0.05), although several pro-inflammatory cytokines were not quantifiable in any group. In conclusion, the data demonstrated that spilanthol effectively reduced inflammation in a mouse model of intestinal mucositis induced by 5-FU, and that the compound might be a promising therapeutic candidate for the prevention and treatment of this condition.

Key words

spilanthol - Acmella oleracea - Compositae - intestinal mucositis - 5-fluorouracil - chemotherapy

Full Text

References

References
1 Vanhoecke B, Bateman E, Mayo B, Vanlancker E, Stringer A, Thorpe D, Keefe D. Dark Agouti rat model of chemotherapy-induced mucositis: establishment and current state of the art. Exp Biol Med 2015; 240: 725-741
2 Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004; 4: 277-284
3 Al-Dasooqi N, Sonis ST, Bowen JM, Bateman E, Blijlevens N, Gibson RJ, Logan RM, Nair RG, Stringer AM, Yazbeck R, Elad S, Lalla RV, Mascc I. Emerging evidence on the pathobiology of mucositis. Support Care Cancer 2013; 21: 3233-3241
4 Duncan M, Grant G. Review article: oral and intestinal mucositis – causes and possible treatments. Aliment Pharmacol Ther 2003; 18: 853-874
5 Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol 2015; 27: 159-164
6 Cinausero M, Aprile G, Ermacora P, Basile D, Vitale MG, Fanotto V, Parisi G, Calvetti L, Sonis ST. New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury. Front Pharmacol 2017; 8: 354
7 Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, des Varannes SB, Le Vacon F, de La Cochetiere MF. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis – current evidence and potential clinical applications. Aliment Pharmacol Ther 2014; 40: 409-421
8 Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM. Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered?. Cancer Chemother Pharmacol 2009; 63: 239-251
9 Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3: 330-338
10 Lee JJ, Beumer JH, Chu E. Therapeutic drug monitoring of 5-fluorouracil. Cancer Chemother Pharmacol 2016; 78: 447-464
11 Wu ZQ, Han XD, Wang Y, Yuan KL, Jin ZM, Di JZ, Yan J, Pan Y, Zhang P, Huang XY, Wang ZG, Zheng Q. Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice. Cancer Chemother Pharmacol 2011; 68: 87-96
12 Yasuda M, Kato S, Yamanaka N, Iimori M, Utsumi D, Kitahara Y, Iwata K, Matsuno K, Amagase K, Yabe-Nishimura C, Takeuchi K. Potential role of the NADPH oxidase NOX1 in the pathogenesis of 5-fluorouracil-induced intestinal mucositis in mice. Am J Physiol Gastrointest Liver Physiol 2012; 302: G1133-G1142
13 Pereira VBM, Melo AT, Assis EM, Wong DVT, Brito GAC, Almeida PRC, Ribeiro RA, Lima RCP. A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice. Cancer Chemother Pharmacol 2016; 77: 323-332
14 Sano T, Utsumi D, Amagase K, Matsumoto K, Tominaga M, Higuchi K, Takeuchi T, Kato S. Lafutidine, a histamine h2 receptor antagonist with mucosal protective properties, attenuates 5-fluorouracil-induced intestinal mucositis in mice through activation of extrinsic primary afferent neurons. J Physiol Pharmacol 2017; 68: 79-90
15 Yeung CY, Chan WT, Jiang CB, Cheng ML, Liu CY, Chang SW, Chiau JSC, Lee HC. Amelioration of chemotherapy-induced intestinal mucositis by orally administered probiotics in a mouse model. PLoS One 2015; 10: e0138746
16 Bastos CCC, de Avila PHM, dos Santos EX, de Avila RI, Batista AC, Fonseca SG, Lima EM, Marreto RN, de Mendonca EF, Valadares MC. Use of Bidens pilosa L. (Asteraceae) and Curcuma longa L. (Zingiberaceae) to treat intestinal mucositis in mice: toxico-pharmacological evaluations. Toxicol Reports 2016; 3: 279-287
17 Chen XX, Lam KH, Chen QX, Leung GPH, Tang SCW, Sze SCW, Xiao JB, Feng F, Wang Y, Zhang KYB, Zhang ZJ. Ficus virens proanthocyanidins induced apoptosis in breast cancer cells concomitantly ameliorated 5-fluorouracil induced intestinal mucositis in rats. Food Chem Toxicol 2017; 110: 49-61
18 Bajic JE, Eden GL, Lampton LS, Cheah KY, Lymn KA, Pei JV, Yool AJ, Howarth GS. Rhubarb extract partially improves mucosal integrity in chemotherapy-induced intestinal mucositis. World J Gastroenterol 2016; 22: 8322-8333
19 Paulraj J, Govindarajan R, Palpu P. The genus spilanthes ethnopharmacology, phytochemistry, and pharmacological properties: a review. Adv Pharmacol Sci 2013; 2013: 510298
20 Cilia-Lopez VG, Juarez-Flores BI, Aguirre-Rivera JR, Reyes-Agueero JA. Analgesic activity of Heliopsis longipes and its effect on the nervous system. Pharm Biol 2010; 48: 195-200
21 Escobedo-Martinez C, Guzman-Gutierrez SL, Hernandez-Mendez MD, Cassani J, Trujillo-Valdivi A, Orozco-Castellanos LM, Enriquez RG. Heliopsis longipes: anti-arthritic activity evaluated in a Freundʼs adjuvant-induced model in rodents. Rev Bras Farm J Pharmacogn 2017; 27: 214-219
22 Rios MY, Aguilar-Guadarrama AB, del Carmen Gutierrez M. Analgesic activity of affinin, an alkamide from Heliopsis longipes (Compositae). J Ethnopharmacol 2007; 110: 364-367
23 Nomura ECO, Melissa R, da Silva CF, Hamm LA, Nascimento AM, de Souza LM, Cipriani TR, Baggio CH, Werner MFD. Antinociceptive effects of ethanolic extract from the flowers of Acmella oleracea (L.) RK Jansen in mice. J Ethnopharmacol 2013; 150: 583-589
24 de la Rosa-Lugo V, Acevedo-Quiroz M, Deciga-Campos M, Rios MY. Antinociceptive effect of natural and synthetic alkamides involves TRPV1 receptors. J Pharm Pharmacol 2017; 69: 884-895
25 Maioli TU, de Melo Silva B, Dias MN, Paiva NC, Cardoso VN, Fernandes SO, Carneiro CM, Dos Santos Martins F, de Vasconcelos Generoso S. Pretreatment with Saccharomyces boulardii does not prevent the experimental mucositis in Swiss mice. J Negat Results Biomed 2014; 13: 6
26 Chen YL, Zheng H, Zhang JZ, Wang L, Jin ZX, Gao WY. Protective effect and potential mechanisms of Wei-Chang-An pill on high-dose 5-fluorouracil-induced intestinal mucositis in mice. J Ethnopharmacol 2016; 190: 200-211
27 Kato S, Hamouda N, Kano Y, Oikawa Y, Tanaka Y, Matsumoto K, Amagase K, Shimakawa M. Probiotic bifidobacterium bifidum G9-1 attenuates 5-fluorouracil-induced intestinal mucositis in mice via suppression of dysbiosis-related secondary inflammatory responses. Clin Exp Pharmacol Physiol 2017; 44: 1017-1025
28 Li HL, Lu L, Wang XS, Qin LY, Wang P, Qiu SP, Wu H, Huang F, Zhang BB, Shi HL, Wu XJ. Alteration of gut microbiota and inflammatory cytokine/chemokine profiles in 5-fluorouracil induced intestinal mucositis. Front Cell Infect Microbiol 2017; 7: 455
29 dos Santos EX, Avilaa PHM, Bastos CCC, Batista AC, Naves LN, Marreto RN, Lima EM, Mendonca EF, Valadares MC. Curcuminoids from Curcuma longa L. reduced intestinal mucositis induced by 5-fluorouracil in mice: bioadhesive, proliferative, anti-inflammatory and antioxidant effects. Toxicol Reports 2016; 3: 55-62
30 Logan RM, Stringer AM, Bowen JM, Yeoh ASJ, Gibson RJ, Sonis ST, Keefe DMK. The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev 2007; 33: 448-460
31 Wu L, Fan N, Lin M, Chu I, Huang S, Hu CY, Han S. Anti-inflammatory effect of spilanthol from Spilanthes acmella on murine macrophage by down-regulating LPS-Induced inflammatory mediators. J Agric Food Chem 2008; 56: 2341-2349
32 de Freitas Blanco VS, Michalak B, Zelioli ÍAM, da Silva Santos de Oliveira A, Rodrigues MVN, Ferreira AG, Garcia VL, Cabral FA, Kiss AK, Rodrigues RAF. Isolation of spilanthol from Acmella oleracea based on Green Chemistry and evaluation of its in vitro anti-inflammatory activity. J Supercrit Fluids 2018; 140: 372-379
33 Masoodi I, Tijjani BM, Wani H, Hassan NS, Khan AB, Hussain S. Biomarkers in the management of ulcerative colitis: a brief review. Ger Med Sci 2011; 16: Doc03
34 Song MK, Park MY, Sung MK. 5-Fluorouracil-induced changes of intestinal integrity biomarkers in BALB/c mice. Cancer Prev 2013; 18: 322-329
35 Miyamoto H, Kanayama T, Horii K, Kawai T, Tsuchimochi T, Shigetomi T, Shibamoto Y, Shibuya Y. The relationship between the severity of radiation-induced oral mucositis and the myeloperoxidase levels in rats. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 120: 329-336
36 Hamouda N, Sano T, Oikawa Y, Ozaki T, Shimakawa M, Matsumoto K, Amagase K, Higuchi K, Kato S. Apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of 5-fluorouracil-induced intestinal mucositis in mice. Basic Clin Pharmacol Toxicol 2017; 121: 159-168
37 Krawisz JE, Sharon P, Stenson WF. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity – assessment of inflammation in rat and hamster models. Gastroenterology 1984; 87: 1344-1350

Supplementary Material

Supporting Information