Pharmacological Evaluation of Ivermectin in Chemically Induced Rat Model of Oral Cancer

Abstract

Introduction Oral cancer or mouth cancer is the cancer of the oral cavity that involves lips, linings of cheeks, tongue, gingiva, teeth, and palates. It is the highly widespread subtype of head and neck cancer which ranks sixth most common cancer globally. Squamous cell carcinoma accounts for more than 90% of oral cancer. The prevalence of oral malignancy has been constantly increasing since a decade. Ivermectin has been approved by FDA in 1987 originally as an antiparasitic agent in humans. In the course of recent years, numerous studies have suggested that ivermectin may also be used as an anti-cancer agent. Many experiments have been performed on leukaemia, glioblastoma, ovarian cancer, breast cancer, and neurofibromatosis type 2 (NF2) tumours showing its activity as an anti-cancer agent. Although, the antitumor action of ivermectin continues to be clarified at the molecular level, that is significant for discovering the particular types of cancer which are responsive to this drug.. Objectives: In the light of above mentioned facts, the objectives of the present study were as follows: 1. To investigate the pharmacological action of Ivermectin in 4-Nitroquinoline-1-oxide induced oral cancer in rats 2. To study the possible mechanism of action of Ivermectin for its anti-cancer activity against oral cancer. Materials and Method Oral cancer was induced chemically by 4-Nitroquinoline-1-oxide (4-NQO) in wistar rats. 4-NQO was dissolved in propylene glycol to make 0.5 % of the solution and the solution was directly applied on the tongue of the rats thrice a week for approximately 10-12 weeks. The treatment with Ivermectin was initiated from 10thweek by administering different doses of Ivermectin alone and in combination with 5-fluorouracil (standard drug). Ivermectin was administered via intraperitoneal for 30 days (4 weeks) daily and 5-fluorouracil (24.5 mg/kg) twice a week for 4 weeks via i.p route. At the end of 14th weeks, the animals were sacrificed and the tongue tissues were isolated from different groups for the evaluation of various parameters. Physical parameters (body weight, food and water intake), tumour parameters (tumour volume and tumour burden), tumor specific parameters (caspase 3, VEGF-A, TGF-beta and p53), inflammatory markers (IFN- γ, IL-1 β) and histopathological studies were carried out. Results Tumor specific parameters There was significant (p<0.001) increase in the levels of Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor beta (TGF-β) in Disease Control group as compared to normal control group and a significantly decrease in VEGF and TGF-β levels were seen in animal treated with Ivermectin and 5-fluorouracil 24.5 mg/kg as compared to Disease Control. There was significant (p<0.001) decrease in the levels of caspase 3 (cas 3) and tumour suppressor gene (p53) in Disease Control group as compared to normal control group and a significantly increase in cas 3 and p53levels were seen in animal treated with Ivermectin and 5-fluorouracil 24.5 mg/kg as compared to Disease Control. Inflammatory markers evaluation The disease control group showed significant (p<0.001) increase in the inflammatory levels as compared to the normal control group. Animals treated with Ivermectin and combination depicted significant (p<0.001) reduction in levels of inflammatory markers. Conclusion: In-vivo studies of Ivermectin in oral cancer showed potential anticancer effects. Highly significant effects were only obtained at the highest dose of Ivermectin and combination (5 mg/kg Ivermectin and in combination with 24.5 mg/kg 5-Fluorouracil). From these studies, we can say that Ivermectin exhibits anti-cancer effect in oral cancer.