title: An Acetamide Derivative as a Camptothecin Sensitizer for Human Non-Small-Cell Lung Cancer Cells through Increased Oxidative Stress and JNK Activation.
abstract: In recent years, combination chemotherapy is a primary strategy for treating lung cancer; however, the issues of antagonism and side effects still limit its applications. The development of chemosensitizer aims to sensitize chemoresistant cancer cells to anticancer drugs and therefore improve the efficacy of chemotherapy. In this study, we examined whether N-[2-(morpholin-4-yl)phenyl]-2-{8-oxatricyclo[7.4.0.0,2,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yloxy}acetamide (NPOA), an acetamide derivative, sensitizes human non-small-cell lung cancer (NSCLC) H1299 cells towards camptothecin- (CPT-) induced apoptosis effects. Our results demonstrate that the combination of CPT and NPOA enhances anti-lung-cancer effect. The cytometer-based Annexin V/propidium iodide (PI) staining showed that CPT and NPOA cotreatment causes an increased population of apoptotic cells compared to CPT treatment alone. Moreover, Western blotting assay showed an enhancement of Bax expression and caspase cascade leading to cell death of H1299 cells. Besides, CPT and NPOA cotreatment-mediated disruption of mitochondrial membrane potential (MMP) in H1299 cells may function through increasing the activation of the stressed-associated c-Jun N-terminal kinase (JNK). These results showed that NPOA treatment sensitizes H1299 cells towards CPT-induced accumulation of cell cycle S phase and mitochondrial-mediated apoptosis through regulating endogenous ROS and JNK activation. Accordingly, NPOA could be a candidate chemosensitizer of CPT derivative agents such as irinotecan or topotecan in the future.
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Han-Lin
authors.initials: HL
authors.lastname: Chou
authors.affiliation: Department of Thoracic Surgery, Chi-Mei Medical Center, Tainan 710, Taiwan.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fong
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Hsin-Hsien
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Research Center for Environment Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Eing Mei
authors.initials: EM
authors.lastname: Tsai
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Jeff Yi-Fu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Wen-Tsan
authors.initials: WT
authors.lastname: Chang
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Chang-Yi
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: David Wang
authors.affiliation: Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Hurng-Wern
authors.identifier: 0000-0001-5015-3708
authors.initials: HW
authors.lastname: Huang
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Research Center for Environment Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung 402, Taiwan; The Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Chien-Chih
authors.identifier: 0000-0001-7307-2468
authors.initials: CC
authors.lastname: Chiu
mesh_terms: D000072283:A549 Cells; D000081:Acetamides / Q000737:chemistry / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D002166:Camptothecin