Repurposing bosentan as an anticancer agent: EGFR/ERK/c‐Jun modulation inhibits NSCLC tumor growth

Drug repurposing of well-established drugs to be targeted against lung cancer has been a promising strategy. Bosentan is an endothelin 1 (ET-1) blocker widely used in pulmonary hypertension. The current experiment intends to inspect the anticancer and antiangiogenic mechanism of bosentan targeting epidermal growth factor receptor (EGFR) /extra-cellular Signal Regulated Kinase (ERK) /c-Jun/vascular endothelial growth factor (VEGF) carcinogenic pathway. BALB/c mice were randomized into four groups, the first received the vehicle, the second received 100 mg/kg oral bosentan alone, the third has non-small cell lung cancer (NSCLC) induced by two doses of 1.5 g/kg urethane i.p. and finally the fourth has NSCLC received bosentan. To determine the anti-proliferative impact of bosentan, cytokeratin 19 fragments (CYFRA 21-1) level was assessed, and Ki-67 positive cells were counted by immunohistochemical (IHC). Molecular expression of EGFR via IHC, relative expression of p-ERK1/2 and p-c-Jun via western blotting and caspase 3, Bcl-2 Associated X-protein (BAX)/B-cell lymphoma 2 (Bcl-2) ratio and VEGF via ELISA were quantified. Bosentan showed pronounced improvement in lung index and histopathological examinations. Bosentan exerted a noticeable arrest of lung cancer growth indicated by the attenuation of CYFRA 21-1 and Ki-67 positive cell counts besides the boost of BAX/Bcl-2 ratio and caspase 3. Bosentan induced a remarkable decline of EGFR, T-ERK1/2/p-ERK1/2, T-c-Jun/p-c-Jun, and VEGF. Bosentan induced cytotoxic and anti-angiogenic impact through regulation of EGFR/ERK/c-Jun/VEGF axis suggesting its potential therapeutic impact against lung cancer.