Enhancement of chemotherapeutic efficacy via non-canonical autophagy induced by Olea europaea in human model of lung adenocarcinoma cells (A549)

Introduction – Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, with poor prognosis and limited therapeutic efficacy due to drug resistance and off-target effects. Combining natural compounds with conventional chemotherapy is emerging as a promising strategy to enhance anticancer activity while reducing toxicity. Methods – We investigated the effects of an olive fruit extract from Olea europaea L. (OE) combined with 5-fluorouracil (5-FU) or cisplatin (CIS) on human lung adenocarcinoma A549 cells. Analyses included cell viability, autophagy markers, gene expression, ROS levels, and Nrf2 nuclear translocation. Results – Co-treatment with OE and chemotherapeutic agents significantly reduced cell viability and induced non-canonical autophagy, indicated by increased LC3BII and decreased Beclin-1 expression, without activating classical apoptotic markers. Gene expression analysis revealed downregulation of AGR2 and upregulation of GRP78, suggesting modulation of ER stress. ROS levels decreased, and Nrf2 nuclear translocation confirmed activation of the antioxidant response. Discussion – These findings indicate that OE potentiates the therapeutic effects of 5-FU and CIS by promoting alternative cell death pathways and modulating oxidative and ER stress responses. Our results support the potential use of Olea europaea as a safe and effective adjuvant in lung cancer treatment, providing a basis for further preclinical and clinical studies.