Targeting EGFR/PI3K/AKT/mTOR and Bax/Bcl-2/caspase3 pathways with ivermectin mediates its anticancer effects against urethane-induced non-small cell lung cancer in BALB/c mice

Lung cancer's mortality is among the highest compared to other cancers globally. However, a recent study has shown that ivermectin, an antiparasitic drug, may have a promising anticancer effect on lung cancer. The present study aimed to investigate the impact of ivermectin on EGFR. /PI3K/AKT/mTOR signaling pathway in NSCLC. Mice were divided into four groups; (1) normal; (2) oral ivermectin alone (5 mg/kg) daily; (3) NSCLC was induced by urethane (1.5 g/kg, i.p.) at days one and sixty; (4) NSCLC group treated with ivermectin. The effect of ivermectin on macroscopic, microscopic, and lung index was assessed. The antitumor and antiproliferative effects of ivermectin were investigated by CYFRA 21–1 level and Ki-67, respectively. IHC determined the molecular expression of EGFR, while phosphorylated PI3K, AKT, and mTOR were quantified by Western blotting assay. ELISA assay of active caspase 3, Bcl-2B-cell lymphoma 2., and BAX Bcl-2 Associated X-protein. was used to assess the apoptotic effect of ivermectin. Finally, VEGF lung content was measured. Findings showed that ivermectin improved macro and microscopic pathological changes. Ivermectin induced cytotoxic effect as indicated by CYFRA 21–1 suppression besides enhancing BAX/Bcl-2 ratio and active caspase 3. The immunoexpression of Ki-67 and EGFR declined. Ivermectin remarkably reduced p-PI3K, p-AKT, p-mTOR, and VEGF expressions. Overall, the study proposes ivermectin as a promising drug for lung cancer through its orchestral regulation of EGFR/PI3K/AKT/mTOR/VEGF signaling.