Obese mammary tumour-bearing mice are highly sensitive to doxorubicin-induced hepatotoxicity

Abstract

Background Breast cancer is a major health burden for women, worldwide. Lifestyle-related risk factors, such as obesity and being overweight, have reached epidemic proportions and contributes to the development of breast cancer. Doxorubicin (DXR) is a chemotherapeutic drug commonly used to treat breast cancer, and although effective, may cause toxicity to other organs. The mechanisms and effects of DXR on hepatic tissue, and the contributing role of obesity, in breast cancer patients are poorly understood. The aim of this study was therefore to investigate the effects of DXR on hepatic tissue in an obese tumour-bearing mouse model. Methods A diet-induced obesity (DIO) mouse model was established, where seventy-four three-week-old female C57BL6 mice were divided into two main groups, namely the high fat diet (containing 60% kcal fat) and standard diet (containing 10% kcal fat) groups. After eight weeks on their respective diets, the DIO phenotype was established, and the mice were further divided into tumour and non-tumour groups. Mice were subcutaneously inoculated with E0771 triple negative breast cancer cells in the fourth mammary gland and received three doses of 4 mg/kg DXR (cumulative dosage of 12 mg/kg) or vehicle treatments via intraperitoneal injection. The expression levels of markers involved in apoptosis and alanine aminotransferase (ALT) were compared by means of western blotting. To assess the pathology and morphology of hepatic tissue, haematoxylin and eosin staining was performed. The presence of fibrosis and lipid accumulation in hepatic tissues were assessed with Masson’s trichrome and Oil Red O staining, respectively. Results Microscopic examination of liver tissues showed significant changes in the high fat diet tumour-bearing mice treated with DXR, consisting of macrovesicular steatosis, hepatocyte ballooning and lobular inflammation, compared to the standard diet tumour-bearing mice treated with DXR and the control group (standard diet mice). These changes are the hallmarks of non-alcoholic fatty liver disease, associated with obesity. Conclusion The histopathological findings indicated that DXR caused significant hepatic parenchymal injury in the obese tumour-bearing mice. Hepatotoxicity is aggravated in obesity as an underlying co-morbidity. It has been shown that obesity is associated with poor clinical outcomes in patients receiving neo-adjuvant chemotherapy treatment regimens.

Metabolomics and Network Analyses Reveal Phenylalanine and Tyrosine as Signatures of Anthracycline-Induced Hepatotoxicity

“…Regardless of the exact mechanism, the observed reduction in hepatic phenylalanine and tyrosine levels could have important implications for cancer treatment, particularly for breast cancer patients who have a high incidence of AIH [ 9 ]. On the one hand, these two metabolites could potentially serve as biomarkers for predicting the development of AIH.…”

“…Treating patients receiving anthracyclines who develop hepatotoxicity requires a solid understanding of the toxicity mechanism. Previous studies have shown significant structural abnormalities (e.g., hepatocyte vacuolation and focal necrosis) and various Pharmaceuticals 2023, 16, 797 2 of 13 biochemical alterations (e.g., elevated levels of serum aminotransferases and free radicals) in the livers of animal models treated with DOX [9,10]. The molecular insight into AIH indicates a key role of oxidative stress through the production of reactive oxygen species (ROS), which occurs during the hepatic metabolism of anthracyclines [11].…”

Influence of doxorubicin on the extracellular matrix of the liver of rats under conditions of chronic alcoholic hepatitis

“…A decrease in the concentration of the chondroitin fraction of glycosaminoglycans in the alcohol hepatitis group may be a consequence of a decrease in decorin content and a sign of the inflammatory process in the liver (Li et al, 2023). An increase in the concentration of the chondroitin fraction of glycosaminoglycans in the liver in injection of doxorubicin during alcoholic hepatitis group may be a sign of the combination of toxic effects of these substances and threaten the development of liver fibrosis (Dudás et al, 2001;Sedeman et al, 2022).…”