title: NBM-T-BMX-OS01, an Osthole Derivative, Sensitizes Human Lung Cancer A549 Cells to Cisplatin through AMPK-Dependent Inhibition of ERK and Akt Pathway.
abstract: BACKGROUND
  Drug combination therapies using cisplatin and natural products are common practice in the treatment of human lung cancer. Osthole is a natural compound extracted from a number of medicinal plants and has been shown to exert strong anticancer activities with low toxicity.
  
  
  METHODS
  In the present study, NBM-T-BMX-OS01 (BMX), derived from the semi-synthesis of osthole, was evaluated in cisplatin treated A549 cells to investigate its effect on cisplatin resistance in human lung cancer. The anticancer effect of BMX were measured by cell viablity' colony formation' TUNEL staining' flow cytometry and cell cycle assay. The fluorescence staining was performed to detect intracellular and mitochondrial reactive oxygen species (ROS) generation. Western blot analysis, antagonists pretreatment and small interfering RNA (siRNA) transfection were used to determine the potential mechanism.
  
  
  RESULTS
  It was found that, in comparison with single cisplatin treatment, the combination of BMX and cisplatin resulted in greater efficacy in inhibition of proliferation and colony formation, apoptosis induction and cell cycle arrest. The results of fluorescence staining showed that the combination effect of BMX and cisplatin was due to oxidative stress induced by mitochondrial ROS generation. In addition, BMX significantly attenuated the phosphorylation of ERK and Akt, two important pro-survival kinases. In contrast, BMX inhibited the activation of AMPK, and knockdown of AMPK using specific siRNA partially reversed BMX-induced inhibition of ERK and Akt, as well as its synthetic effects on cisplatin induced anticancer activity in A549 cells.
  
  
  CONCLUSIONS
  Taken together, this study provides that BMX might modulate cisplatin resistance through AMPK-ERK and AMPK-Akt pathways. These results also support the role of BMX as a potential drug candidate for use in combination with cisplatin in the treatment of human lung cancer.
authors.affiliation: Respiratory Department, The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China.
authors.forename: Tian-Jun
authors.initials: TJ
authors.lastname: Chen
authors.forename: Yue-Fei
authors.initials: YF
authors.lastname: Zhou
authors.forename: Jie-Juan
authors.initials: JJ
authors.lastname: Ning
authors.forename: Tian
authors.initials: T
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Ren
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D003374:Coumarins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases; D002945:Cisplatin; C046627:osthol