Protective Effect of Dimethyl Fumarate on Doxorubicin-induced Genotoxicity in Rats

Background and Purpose Doxorubicin is a broad-spectrum antineoplastic agent; however, however, its genotoxic/cytotoxic effects limit its clinical application. Dimethyl fumarate (DMF) is an FDA-approved oral drug shown to have antioxidant, anti-inflammatory and antimutagenic effects via activating Nrf2 antioxidant pathway. The present study aimed to investigate the possible protective effect of DMF against doxorubicin-induced chromosomal and DNA damage in rat bone marrow cells. Experimental Approach Wistar Albino rats of both sexes were administered DMF orally (15mg/kg once daily for 14 days) alone or with doxorubicin which was injected as a single dose (90 mg/kg at day 14) to induce toxicity. The blood samples were collected 24 hours after doxorubicin’s injection from all groups to measure the serum levels of MDA, GSH, SOD, and GPx1 and bone marrow was harvested to assess chromosomal aberration, micronucleus, and comet assays. Key Results The rats in the doxorubicin-only group exhibited a significant decrease in mitotic index and depleted GSH and antioxidants enzymes serum levels with a significant elevation in MDA serum level, % DNA in Tail, micronucleus appearance and chromosomal aberrations compared to the control group; DMF pretreatment prior to doxorubicin exposure, significantly-reduced % DNA in Tail, micronucleus appearance, and chromosomal aberrations, improved mitotic index, restored GSH level and antioxidant enzymes activity compared doxorubicin-only group. Conclusion and Implication This study revealed that DMF alone has no DNA-damaging or clastogenic activities; DMF has protective effects against the genotoxicity induced by doxorubicin; thus, DMF might be a potential chemoprotective agent against doxorubicin-induced toxicity in cancer chemotherapy