PHARMACOLOGICAL EVALUATION OF HESPERIDIN AND FEBUXOSTAT IN EXPERIMENTALLY INDUCED BREAST CANCER IN RATS

Abstract

Background: Breast cancer is the second most common cause of death among women worldwide after lung cancer. It occurs when certain cells in the breast become abnormal and multiply uncontrollably to form a tumour. This event occurs due to various genetic and environmental factors. These factors are responsible for activating various pathways including Ras/raf, PI3k/Akt and Wnt pathways. Hesperidin, a natural flavone abundantly present in citrus fruit possesses anticancer activity in different cell lines of various cancers like colon, cervical, prostate, lung and breast cancer. However, scanty information is available with respect to its effects on genetic expression in breast cancer. Febuxostat, a non-purine xanthine oxidase inhibitor is prescribed for the treatment of gout. No evidence is available for the beneficial effect of Febuxostat in breast cancer. Aim and objectives: The objectives of the present study was to investigate the pharmacological action and mechanism of action of hesperidin and febuxostat in 7, 12-dimethyl benz[a]anthracene induced breast cancer in female Wistar rats. Materials and Methods: The induction of breast cancer was done by subcutaneous injection of 7, 12-dimethyl benz[a]anthracene (45 mg/kg) in the mammary gland of female Wistar rats. The animals were divided into nine different groups as per the treatment regimen. Doxorubicin was used as a standard treatment (4 mg/kg) whereas hesperidin (30 mg/kg) and febuxostat (4.11 mg/kg) were used as investigational drug. The induction of cancer was done for a period of 12 weeks followed by the treatment with either standard or investigational drugs for a period of 6 weeks. After the completion of treatment, the animals were euthanized using thiopental sodium and the tumours were collected. Tumour specific parameters (tumour volume, tumour burden and tumour inhibition rate), Oxidative stress parameters (superoxide dismutase, glutathione reductase and malondialdehyde levels), Inflammation markers (IL-6, TNF-α and IL-1β) and genetic expression for PTEN were evaluated. Histopathological and Immunohistochemical analysis were also performed. Results: Tumour Specific Parameters: There was significant decrease in tumour volume and tumour burden in doxorubicin treated animals (p<0.001) as compared to the disease control animals. Further, there was significant decrease in tumour volume and tumour burden in hesperidin (p<0.001) and febuxostat (p<0.001) treated animals as compared to the disease control animals. However, there was significant increase in tumour volume and tumour burden in febuxostat treated animals and in the combined therapy of hesperidin (p<0.05) and febuxostat (p<0.01) treated animals as compared to the doxorubicin treated animals. Apart from this, survival rate and tumour inhibition rate were also increased in treated animals as compared to the disease control groups