Development of a Lung Cancer Model in Wistar Rat and In Silico Screening of its Biomarkers

Abstract

Background: Cancer is caused by three factors: Nutrition, inflammation and cigarette smoke. This study in rat experimental models would enable us to understand the mechanism of lung cancer caused by NNK to which humans are continuously exposed, help us understand possible molecular targets, design drugs for humans against lung cancer. Aim: A lung cancer model was developed by administering tobacco specific carcinogen: NNK [4-methylnitrosamino)-1-(3-pyridyl)-1-butanone] to male wistar rats in 24 weeks. Further, In silico approach was followed to screen the molecular targets. Methods: A method was established in which subcutaneous and intraperitoneal injections of NNK were administered to male wistar rats simultaneously. For authentication of lung cancer in vivo we performed molecular docking simulations with protein biomarkers:Cox-2, p53, p38 MAPKs and EGFR using Hex-Discovery Studio, Schrödinger-maestro software. Results: Lung morphology and histopathology indicated the initiation of bronchiolar epithelial hyperplasia, squamous dysplasia beginning in cancer 1 group after 16 weeks NNK exposure. 66.66% incidence of squamous cell carcinoma (SCC), 33.3% incidence of adenocarcinoma in cancer 2 group after being exposed to NNK. Results indicated that the SCC and adenocarcinoma gradually increased from 66.66% to 85.71% in cancer 2 group and 33.33% to 42.58% in cancer 3 groups respectively. Docking results indicate the total binding energy and glide energy of Cox-2, p53, p38 MAPKs, EGFR : 38.14, -211.58, -181.58, - 213.05 Kcal/mol and -39.25, -32.16,-36.49, -40.19 Kcal/mol, respectively. Conclusion: Pulmonary adenocarcinoma developed in 24 weeks, in silico experiments confirm EGFR to be the most potential target for NNK induced lung Cancer.