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

Abstract

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.³/PI3K⁴/AKT^5/mTOR⁶ signaling pathway in NSCLC.⁷ 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 EGFR⁸, while phosphorylated PI3K, AKT, and mTOR were quantified by Western blotting assay. ELISA assay of active caspase 3, Bcl-2⁹, and BAX¹⁰ was used to assess the apoptotic effect of ivermectin. Finally, VEGF¹¹ 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.

Keywords: EGFR; Ivermectin; Lung cancer; PI3K/AKT/mTOR; Urethane; VEGF.