title: Gefitinib-mediated reactive oxygen specie (ROS) instigates mitochondrial dysfunction and drug resistance in lung cancer cells.
abstract: Therapeutic benefits offered by tyrosine kinase inhibitors (TKIs), such as gefitinib (Iressa) and erlotinib (Tarceva), are limited due to the development of resistance, which contributes to treatment failure and cancer-related mortality. The aim of this study was to elucidate mechanistic insight into cellular perturbations that accompany acquired gefitinib resistance in lung cancer cells. Several lung adenocarcinoma (LAD) cell lines were screened to characterize epidermal growth factor receptor (EGFR) expression and mutation profile. To circumvent intrinsic variations between cell lines with respect to response to drug treatments, we generated gefitinib-resistant H1650 clone by long-term, chronic culture under gefitinib selection of parental cell line. Isogenic cells were analyzed by microarray, Western blot, flow cytometry, and confocal and transmission electron microscope. We observed that although chronic gefitinib treatment provided effective action against its primary target (aberrant EGFR activity), secondary effects resulted in increased cellular reactive oxygen species (ROS). Gefitinib-mediated ROS correlated with epithelial-mesenchymal transition, as well as striking perturbation of mitochondrial morphology and function. However, gefitinib treatment in the presence of ROS scavenger provided a partial rescue of mitochondrial aberrations. Furthermore, withdrawal of gefitinib from previously resistant clones correlated with normalized expression of epithelial-mesenchymal transition genes. These findings demonstrate that chronic gefitinib treatment promotes ROS and mitochondrial dysfunction in lung cancer cells. Antioxidants may alleviate ROS-mediated resistance.
authors: From the Section of Molecular Medicine and.
authors: Imoh S
authors: IS
authors: Okon
authors: From the Section of Molecular Medicine and.
authors: Kathleen A
authors: KA
authors: Coughlan
authors: From the Section of Molecular Medicine and.
authors: Miao
authors: M
authors: Zhang
authors: From the Section of Molecular Medicine and.
authors: Qiongxin
authors: Q
authors: Wang
authors: From the Section of Molecular Medicine and the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 ming-hui-zou@ouhsc.edu.
authors: Ming-Hui
authors: MH
authors: Zou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D017382:Reactive Oxygen Species; D000077156:Gefitinib
keywords: Drug Resistance; Epithelial-Mesenchymal Transition (EMT); Gefitinib Resistance; Mitochondria; Mitochondrial Dysfunction; Protein-tyrosine Kinase (Tyrosine-protein Kinase); Reactive Nitrogen Species (RNS); Reactive Oxygen Species (ROS)