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

Abstract

Background: Cancer is usually caused by three factors: Nutrition, inflammation and cigarette smoke. This study on 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, and assist in designing 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 for 24 weeks. Furthermore, 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 and squamous dysplasia in the cancer 1 group after 16 weeks of NNK exposure. 66.66% incidence of squamous cell carcinoma (SCC) and 33.3% incidence of adenocarcinoma were observed in cancer 2 group after being exposed to NNK. Results indicated that the incidence of SCC and adenocarcinoma gradually increased from 66.66% to 85.71% in cancer 2 group and from 33.33% to 42.58% in cancer 3 group, 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 model was developed by administering tobacco-specific carcinogen: NNK [4-methylnitrosamino)-1-(3-pyridyl)-1-butanone] to male Wistar rats in 24 weeks. In silico experiments confirmed EGFR to be the most potential target for NNK induced lung Cancer.