Pharmacological Evaluation of Canagliflozin Againts 7, 12-Dimethyl Benz[A] Anthracene Induced Breast Cancer in Experimental Animal Model

Abstract

Abstract Breast cancer is the second most common cause of death among women worldwide and is responsible for the elevated death rate. Various environmental and genetic factors are responsible for the breast cancer. Different pathways are involved in the breast cancer but the role of Ras/Raf and PI3K/AKT/mTOR pathway is well established in the literature. Based upon this fact PI3K/AKT/mTOR pathway was selected for the present research. Literature search suggested that canagliflozin is the novel SGLT2 inhibitor that showed some anticancer activity against the prostate (22RV1, PC3) and lung (A549, H1299) cancer cell lines. Based upon this fact, the present study was conducted to investigate the anticancer potential of canagliflozin against the breast cancer. Female wistar rats were divided into seven different groups as per the treatment regimen. The induction of breast cancer was carried out by 7, 12-dimethyl benz[a]anthracene (DMBA) (35 mg/kg), subcutaneous route. 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 4 weeks. Doxorubicin was used as standard treatment (2 mg/kg) whereas canagliflozin (100, 200, 300 mg/kg) was used as an investigational drug. After the end of treatment, the animals were euthanized using thiopental sodium and the tumors were collected.The results of our study suggest that the tumor volume was decreased significantly after the administration of doxorubicin alone (2 mg/kg), canagliflozin alone (300mg/kg) and combination of doxorubicin (2 mg/kg) and canagliflozin (100 mg/kg). After the administration of canagliflozin there was a significant decrease in the level of IL-6 was observed. While on the other hand there was a significant increase the level of IL-1β, NF-κB and IFN-γ were observed. The histopathological studies and immunochemistry revealed the antiproliferative activity of canagliflozin which was evident from reduction in tumour inflammation, cell necrosis and inhibition of overexpression of ki-67 protein in doxorubicin treated animals and in combined therapy of doxorubicin and canagliflozin. Also, it was clearly evident that combined therapy of doxorubicin and canagliflozin is more effective. Further studies are warranted in this direction.