The reduction of oxidative stress by nanocomposite Fullerol decreases mucositis severity and reverts leukopenia induced by Irinotecan

Pharmacol Res. 2016 May;107:102-110. doi: 10.1016/j.phrs.2016.03.004. Epub 2016 Mar 15.

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.

Keywords: Enterocytes; Fullerol; Leukopenia; Mucositis; ROS; Tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / adverse effects*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use
  • Fullerenes / therapeutic use*
  • Glutathione / metabolism
  • Ileum / drug effects
  • Ileum / metabolism
  • Ileum / pathology
  • Interleukin-1beta / metabolism
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Irinotecan
  • Leukopenia / chemically induced
  • Leukopenia / prevention & control*
  • Male
  • Melanoma / drug therapy
  • Melanoma / pathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mucositis / chemically induced
  • Mucositis / prevention & control*
  • Nanocomposites / therapeutic use*
  • Oxidative Stress / drug effects
  • Peroxidase / metabolism
  • Thiobarbituric Acid Reactive Substances / metabolism
  • Tumor Burden / drug effects

Substances

  • Antineoplastic Agents, Phytogenic
  • Fullerenes
  • Interleukin-1beta
  • Thiobarbituric Acid Reactive Substances
  • Irinotecan
  • Peroxidase
  • Glutathione
  • Camptothecin