1. Introduction
Doxorubicin (DOX), also known as adriamycin, is an important member of the anthracyclines group of chemotherapeutic drugs; and it has a broad anti-tumour spectrum; where it is used alone or in combination with other chemotherapeutic agents worldwide in the treatment of haematological malignancies, solid tumours, soft tissue sarcomas, small-cell lung, and breast carcinoma; moreover, doxorubicin is also the principal component in the management of Hodgkin’s disease and lymphomas (1). However, the dose-dependent response relation of doxorubicin in many anticancer regimens has been well-defined; an increase in its dose restricts its use due to the development of severe cardiotoxicity, in addition to other cytotoxic effects on normal cells and a substantial negative impact on patient’s health, which poses a significant hurdle in doxorubicin clinical application (2)(3).
The anti-tumour activity of DOX is mediated through its direct intercalating with deoxyribonucleic acid (DNA) and by interfering with the function of many enzymes that are necessary for DNA replication, including topoisomerase-II; where it stabilises the DNA-topoisomerase-II intermediate complex and this, in turn, leads to the distortion of DNA repairing, which consequently results in DNA double-stranded breakage and nuclei fragmentation with condensed chromatin (4)(5).
In addition, oxidative stress (OS) and overproduction of free radicals is an essential part of the doxorubicin mechanism of action, where the metabolism of DOX in the body is mediated by NADPH-dependent cytochrome P-450 that generates free radicals such as semiquinone, quinone, hydrogen peroxide (H2O2), superoxide anion (O2•-), and hydroxyl radical (OH˚ ) which can deplete glutathione and exhaust antioxidants enzymes, increase lipid, protein and nucleic acid peroxidation (6). Furthermore, the lipid peroxidation product malondialdehyde (MDA) can interact with the DNA; this consequently can cause inhibition of DNA replication and chromosomal damage through the formation of DNA adducts; these cytotoxic actions not only affect cancer cells but also can affect normal cells triggering mutation and chromosomal abnormalities including chromosomal aberrations and DNA damage (7)(8). Therefore, enhancing the cellular antioxidant response could reduce doxorubicin-induced oxidative damage.
Dimethyl fumarate (DMF) is a fumaric acid-derived small molecule that exhibits potent antioxidant and anti-inflammatory properties; DMF is a disease-modifying agent under the brand name “Tecfidera” that has been FDA-approved to be used to treat patients with severe psoriasis and relapsing-remitting multiple sclerosis (RRMS) (9). DMF’s antioxidant and anti-inflammatory mechanism of action is thought to involve the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of various genes that regulates antioxidant and detoxification processes (10). The activation of the Nrf2 pathway by DMF has been demonstrated in several studies; DMF treatment showed increased Nrf2 protein levels and gene expression, which was accompanied by increased expression of downstream target genes, including heme oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), reduced Nf-kB, TGF-β signalling and cell senescence (11)(12)(13)(14). The present study was designed to test the possible protective effect of DMF against doxorubicin-induced genotoxicity in rats through the assessment of the extent of chromosomal aberrations (CAs), micronucleus appearance (MN) and mitotic index (MI) in addition to the utilisation of the comet assay a sensitive technique to measure the extent of oxidative DNA damage.