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

Abstract 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.