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.