title: Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts.
abstract: BACKGROUND
  Chromosome Region Maintenance 1 (CRM1) is a nuclear exporter and its inhibitor has anti-tumor activity in various cancers. This study assessed the therapeutic efficiency of the novel CRM1 inhibitor KPT-185 on non-small cell lung cancer (NSCLC).
  
  
  METHODS
  NSCLC cell lines were treated with KPT-185 to assess changes in cell viability, cell cycle, apoptosis, and protein expression. NOD-SCID mice carrying NSCLC cell xenografts were orally treated with KPT-276, a clinical analog of KPT-185, to examine the efficacy and side effects of KPT-276 in vivo.
  
  
  RESULTS
  KPT-185 significantly reduced the viability of six NSCLC cell lines in a time- and dose-dependent manner, including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant H1975 and H1650GR cell lines. In addition, KPT-185 induced these NSCLC cells to arrest at G1 phase of the cell cycle and caused apoptosis in a dose-dependent manner. KPT-185 treatment also reduced CRM1 protein levels in six NSCLC cell lines, and the reduction could be completely abolished by the proteasome inhibitor bortezomib. KPT-185 activated caspase 3, 8, and 9, but inhibited survivin expression in NSCLC cells. In a mouse H1975 cell xenograft model, tumor growth was significantly inhibited by oral KPT-276 administration, and there was no significant mouse body weight loss or other side effects.
  
  
  CONCLUSIONS
  The current study demonstrated the anti-tumor effects of KPT-185 in NSCLC cells, including EGFR-TKI-resistant NSCLC cell lines. Further studies will assess anti-tumor activity of KPT-185 in a clinical trial for NSCLC patients.
authors.affiliation: Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Yuankai
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000179:Acrylates / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D020169:Caspases; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185