Abstract
BackgroundDoxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer. However, chronic cardiotoxicity and multidrug resistance limit the chemotherapeutic use of DOX.MethodsThis study aimed to evaluate the capability of calcium channel blocker diltiazem (DIL) to reverse DOX resistance in breast cancer MCF-7 cells and to confer protection against DOX-induced cardiotoxicity in Wistar rats. For this purpose, we explored the effects of DOX on cell cycle phase distribution and expression of ABCB1, FOXO3a, and p53 genes in the presence and absence of DIL (20 μg/ml) and studied the ability of DIL to prevent DOX-induced cardiotoxicity after a single injection of DOX (15 mg/kg) in male Wister rats.ResultsWe found that compared with DOX alone treatment, DIL + DOX treatment down regulated the ABCB1 gene expression by > fourfold but up regulated the FOXO3a and p53 genes expression by 1.5 fold. DIL treatment conferred protection against DOX-induced cardiotoxicity, as indicated by a decrease in the levels of the cardiac enzyme creatine kinase MB and malondialdehyde and an increase in the total antioxidant capacity and glutathione peroxidase levels. These biochemical results were further confirmed by the histopathological investigation of cardiac cells, which showed normal cardiac cells with central vesicular nuclei and prevention of DOX-induced disruption of normal cardiac architecture in the DIL to DOX group.ConclusionsTaken together, our results indicate that DIL treatment can reverse the resistance of breast cancer cells to the therapeutic effects of DOX and can protect against DOX-induced cardiotoxicity in rats.
Highlights
Doxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer
We evaluated the protective effect of DIL against DOX-induced cardiotoxicity in Wistar rats by evaluating total antioxidant capacity (TAC) and the levels of creatine kinase-MB (CK-MB), glutathione peroxidase (GPx), and malondialdehyde (MDA) and by performing histopathological investigation of cardiac tissue
We studied the possible modulatory mechanisms changes in cell cycle phase distribution, the molecular mechanism of inhibition of ABCB1 gene expression responsible for drug transport as well as expression of the tumor suppressor genes FOXO3a and p53
Summary
Doxorubicin (DOX) is one of the most important anticancer agents used in treating breast cancer. As with other anticancer agents, the clinical use of DOX is hindered by tumor resistance and toxicity to healthy tissues [5]. Resistance to this drug is common, representing the main obstacle to the effective treatment of the disease [6, 7]. To counter MDR to the effects of breast cancer therapeutics, a wide range of compounds capable of inhibiting the MDR gene have been studied. Such inhibitors include, but are not limited to, the anti-HIV protease inhibitors ritonavir and nelfinavir, fumitremorgin C, and biochanin A. We evaluated the protective effect of DIL against DOX-induced cardiotoxicity in Wistar rats by evaluating total antioxidant capacity (TAC) and the levels of creatine kinase-MB (CK-MB), glutathione peroxidase (GPx), and malondialdehyde (MDA) and by performing histopathological investigation of cardiac tissue
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