Pharmacological Evaluation of Sulfadoxine in Chemically Induced Lung Cancer in Mice

Abstract

is one of the leading death modalities amongst all type of cancers. Occurrence and mortality rates due to lung cancer are increasing worldwide. Conventional treatment of lung cancer involves radiation therapy, radiation therapy, chemotherapy immunotherapy and surgery. Ideally, to achieve better efficacy, two or more drugs are combined. Additionally, this treatment options are also believed to result in worsening of the symptoms and evolution of resistance that eventually causing lethality or mortality. Nevertheless, considering such demerits accentuate the need of newer molecules against lung cancer. Anti-malarial agents are being evaluated for their potential role in various cancers which are proved to have promising therapeutic effects. Sulfadoxine, belonging to the anti-folate and anti-malarial class of agent has been suggested to exert anti-tumor effects via acting on anti-folate pathway by inhibiting dihydropteroic acid which will further inhibit the formation of DNA, RNA and other proteins. Objective: However, there are no evidences of any studies carried out on lung cancer, and hence the objective of the presented research is: 1) To investigate pharmacological impacts of Sulfadoxine in Benzo [a] pyrene induced lung cancer. 2) To study the possible mechanism of action of Sulfadoxine as anti-cancer drug in lung cancer. Materials and Methods:Lung Cancer was chemically induced by Benzo [alpha] pyrene (B[a]P) in adult albino mice of 5-8 weeks having weigh approximately between 25-30g were selected for the study. Mice were divided into eight groups. Lung cancer was induced by B[a]P 25 mg/kg orally four times in eight days for 35 days by oral gavage. The treatment was initiated after three months of last dose of B[a]P. Sulfadoxine was given in three different doses (500 mg/kg, 800 mg/kg and 1000 mg/kg by oral route) alone and was also co-administered along with Paclitaxel (standard drug). Sulfadoxine was given orally for 30 days (4 weeks) daily and paclitaxel was administered via i.p route at a total dose of 30 mg/kg/week (equivalent to human dose of 100 mg/m2) from 16th week for three consecutive weeks. At the end of 20 weeks, the animals were sacrificed and the lung tissues were isolated from different groups for the evaluation of various parameters. Physical parameters (body weight, food and water intake), inflammatory markers (IFN- γ, IL-1 β), expression of caspase 3, p53, VEGF A, TGF-beta 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 sulfadoxine 500 mg alone and in combination with paclitaxel 30 mg/kg as compared to Disease Control. There was significant (p<0.001) decrease in the levels of caspase 3 and p53 in disease Control group as compared to normal control group and a significantly increase in caspase 3 and p53 levels were seen in animal treated with sulfadoxine 500 mg alone and in combination with paclitaxel 30 mg/kg as compared to Disease Control. Inflammatory marker evaluation The disease control group showed significant (p<0.001) increase in the inflammatory levels of Interferon Gamma (IFN- γ) and Interleukin-1 beta (IL-1 β) as compared to the normal control group. Animals treated with Sulfadoxine and combination depicted significant (p<0.001) reduction in levels of inflammatory markers. There was significant decrease of inflammatory markers in animals treated with sulfadoxine alone and with paclitaxel.Conclusion: Our data suggest that Sulfadoxine produces potential anticancer effect on B[a]P induced lung cancer in mice and also along with paclitaxel, sulfadoxine shows significant effect. Highly significant effects were only obtained at the 500 mg dose of sulfadoxine along with combination of 30mg/kg paclitaxel. In addition to that it acts as anti-proliferative and reduces inflammation in lung carcinogenesis. Thus, our study suggests that sulfadoxine may be given as adjuvant therapy with paclitaxel to have better therapeutic effects.