title: The reduction of oxidative stress by nanocomposite Fullerol decreases mucositis severity and reverts leukopenia induced by Irinotecan.
abstract: Irinotecan is a useful chemotherapeutic agent for the treatment of several solid tumors. However, this therapy is associated with side effects, including leukopenia and mucositis. Reactive oxygen species (ROS) activate inflammatory pathways and contribute to Irinotecan-induced mucositis. Fullerol is a nanocomposite with anti-oxidant properties that may reduce tissue damage after inflammatory stimuli. In this paper, the effects of Fullerol and mechanisms of protection were investigated in a model of Irinotecan-induced mucositis. Mucositis was induced by an injection of Irinotecan per 4 days in C57BL/6. Fullerol or a vehicle was injected every 12h. On day 7, the intestines were removed to evaluate histological changes, leukocyte influx, and the production of cytokines and ROS. Irinotecan therapy resulted in weight loss, an increased clinical score and intestinal injury. Treatment with Fullerol attenuated weight loss, decreased clinical score and intestinal damage. Irinotecan also induced increased ROS production in enterocytes, oxidative stress, IL-1β production, neutrophil and eosinophil influx in the ileum. Fullerol treatment decreased production of ROS in the enterocytes, oxidative stress, IL-1β production, neutrophil and eosinophil influx in the ileum. Irinotecan therapy also induced leukopenia in an ROS-dependent manner because leukopenia reverted in WT mice treated with Fullerol or Apocynin or in Gp91phox(-/-) mice. Mice treated with Irinotecan presented less melanoma tumor growth compared to the control group. Fullerol does not interfere in the anti-tumor action of Irinotecan. Fullerol has a great pharmacology potential to decreases the severity of mucositis and of leukopenia during chemotherapy treatment.
authors.affiliation: Laboratório Interação Micro-organismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil.
authors.forename: Raquel Duque Nascimento
authors.initials: RDN
authors.lastname: Arifa
authors.affiliation: Laboratório Interação Micro-organismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil.
authors.forename: Talles Prosperi de
authors.initials: TP
authors.lastname: Paula
authors.affiliation: Laboratório Interação Micro-organismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil.
authors.forename: Mila Fernandes Moreira
authors.initials: MFM
authors.lastname: Madeira
authors.affiliation: Laboratório Interação Micro-organismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil.
authors.forename: Renata Lacerda
authors.initials: RL
authors.lastname: Lima
authors.affiliation: Laboratório Interação Micro-organismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil.
authors.forename: Zélia Menezes
authors.initials: ZM
authors.lastname: Garcia
authors.affiliation: Laboratório Interação Micro-organismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil.
authors.forename: Thiago Vinícius
authors.initials: TV
authors.lastname: Ÿvila
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil; Núcleo de Estudos em Inflamação, Departamento de Morfologia, Belo Horizonte, MG, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pinho
authors.affiliation: Laboratório de Angiogênese, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Belo Horizonte, MG, Brazil.
authors.forename: Lucíola Silva
authors.initials: LS
authors.lastname: Barcelos
authors.affiliation: Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Maurício Veloso Brant
authors.initials: MVB
authors.lastname: Pinheiro
authors.affiliation: Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Luiz Orlando
authors.initials: LO
authors.lastname: Ladeira
authors.affiliation: Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Klaus
authors.initials: K
authors.lastname: Krambrock
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil.
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Laboratório Interação Micro-organismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil. Electronic address: souzadg@gmail.com.
authors.forename: Danielle Glória
authors.initials: DG
authors.lastname: Souza
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D037741:Fullerenes / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077146:Irinotecan; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052016:Mucositis / Q000139:chemically induced / Q000517:prevention & control*; D053761:Nanocomposites / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D037741:Fullerenes; D053583:Interleukin-1beta; D017392:Thiobarbituric Acid Reactive Substances; D000077146:Irinotecan; D009195:Peroxidase; D005978:Glutathione; D002166:Camptothecin
keywords: Enterocytes; Fullerol; Leukopenia; Mucositis; ROS; Tumor