Exercise or Metformin Modulates Doxorubicin Mediated Iron Dysregulation in Liver, Heart and Skeletal Muscle

Abstract

Doxorubicin (DOX) is a chemotherapeutic drug used in the treatment of various types of cancer. DOX is known to bind iron, which causes iron dysregulation, mitochondrial disruption, and oxidative stress. Although DOX is known to bind iron in vitro, its effects on iron regulation have yet to be studied comprehensively in animal models. Metformin (MET) and Exercise (EX) have been shown to prevent side effects due to DOX treatment, but their effects on iron regulation are unknown. The purpose of this study is to determine how DOX‐treatment disrupts iron regulation in mouse models and whether pre‐treatment with either MET or EX will ameliorate these effects. Mice were randomly assigned to 6 treatment groups: control, DOX, MET, DOX+MET, EX, and DOX+EX. Mice treated with DOX were given one dose at 15 mg/kg and sacrificed 3 days later. Mice treated with MET were given 500 mg/kg beginning 2 days before DOX treatment and daily until sacrifice. Mice assigned to the exercise treatment group were given an exercise regimen beginning 5 days before DOX treatment and ending on the day of treatment. The mice were exercised for 60 min/day at 70% max speed. Muscle, liver and heart samples were homogenized, and protein quantities were evaluated using Western Blotting. In this study, ferritin heavy chain (FHC) and transferrin receptor (TfR) were measured in liver, skeletal muscle and cardiac tissue. FHC is a protein known to store iron in a non‐reactive way in cells, and TfR is a protein that participates in allowing iron to enter the cell. As hypothesized, DOX treatment caused ~3 fold increase in FHC (p<0.05), and ~2 fold decrease in TfR (p<0.05) in cardiac tissue. In skeletal muscle, DOX caused ~2 fold increase in FHC (p<0.05) and ~4 fold decrease in TfR (p<0.05). There was also ~3 fold increase (p<0.05) in FHC in the liver. The effects of DOX were partially ameliorated in skeletal muscle from mice in the EX group with ~2 fold increase in TfR (p<0.05), while in liver, addition of EX treatments to DOX showed ~4 fold decrease in TfR expression (p<0.05) and DOX +MET showed ~3 fold decrease in TfR (p<0.05). No effect of iron regulation was seen in the heart with EX and MET treatments. These results show that DOX causes changes in iron regulation in all three types of tissue. EX and MET treatments were able to blunt some of these changes in skeletal muscle tissue, and to lower TfR in liver tissue, but no changes were seen in cardiac tissue. Since iron dysregulation was only partially prevented by EX and MET treatment. These data suggest that much of the protective effects of MET and EX against DOX are not in iron regulation. Future studies could further investigate the effects of DOX on iron regulation and its association with oxidative stress, as well as other possible treatments in combination with EX and MET to ameliorate the toxic side‐effects of DOX.Support or Funding InformationMentoring Environment Grant, Brigham Young UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.