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Background/aim: Chemoresistance to paclitaxel (PTX) significantly ameliorates therapeutic efficacy in patients with non-small cell lung cancer (NSCLC), especially in advanced stages, deteriorating the progression free and overall survival rates. One of the critical mechanisms contributing to drug resistance is the excretion of PTX from target cells via efflux pumps. Ivermectin was developed as a bactericidal agent against parasites; however, it has recently been shown to inhibit the proliferation of human cancer cells. Hence, we aimed to evaluate the therapeutic potential of ivermectin in combination with PTX and investigate the molecular mechanisms by which ivermectin overcomes PTX resistance., Materials and Methods: We assessed the antitumor effects of ivermectin in A549 cells treated with or without PTX. We also established PTX-resistant cells using this cell line and explored the underlying mechanisms. Additionally, we evaluated whether ivermectin attenuates PTX-resistance with the retrieval of drug sensitivity., Results: Combined treatment of A549 cells with PTX and ivermectin inhibited cell growth. These cells acquired chemoresistance upon long-term exposure to gradually increasing PTX concentrations, which was accompanied by ABCB1 mRNA up-regulation, and subsequent overproduction of P-glycoprotein (P-gp). Consistent with this, P-gp over-expression resulted in a PTX-resistant phenotype. Notably, the simultaneous ivermectin treatment during the gradual exposure completely abolished P-gp expression, leading to an increased intracellular PTX concentration and sustained PTX sensitivity. Ivermectin was found to regulate P-gp expression via the EGFR/ERK/Akt/NF-[Formula: see text]B pathway., Conclusion: Combined treatment of PTX-resistant A549 cells with ivermectin and PTX may circumvent PTX resistance caused by P-gp induction, highlighting a novel therapeutic avenue for drug repurposing., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)