title: Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin.
abstract: Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.
authors.affiliation: Ph.D. Program in Translational Medicine, National Taiwan University and Academia Sinica , Taipei, Taiwan.
authors.forename: Ting-Chun
authors.initials: TC
authors.lastname: Kuo
authors.affiliation: Department of Chemistry, National Taiwan University , Taipei 106, Taiwan.
authors.forename: Ling-Wei
authors.initials: LW
authors.lastname: Li
authors.affiliation: Ph.D. Program in Translational Medicine, National Taiwan University and Academia Sinica , Taipei, Taiwan.|Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University , Taipei 100, Taiwan.|Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica , Taipei 106, Taiwan.
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.affiliation: Department of Chemistry, National Taiwan University , Taipei 106, Taiwan.
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.affiliation: Department of Life Sciences, National Chung Hsing University , Taichung 402, Taiwan.|Institute of Genomics and Bioinformatics, National Chung Hsing University , Taichung 402, Taiwan.|Agricultural Biotechnology Center, National Chung Hsing University , Taichung 402, Taiwan.|Rong Hsing Research Center for Translational Medicine, National Chung Hsing University , Taichung 402, Taiwan.
authors.forename: Jyung-Hurng
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Genomics Research Center, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Ting-Jen
authors.initials: TJ
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, National Taiwan University College of Medicine , Taipei 100, Taiwan.|Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital Taipei 105, Taiwan.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, National Taiwan University College of Medicine , Taipei 100, Taiwan.
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Hung
authors.affiliation: Institute of Statistical Science, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan 701, Taiwan.
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University , Taipei 100, Taiwan.
authors.forename: Yuan-Ling
authors.initials: YL
authors.lastname: Hsu
authors.affiliation: Genomics Research Center, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 115, Taiwan.|NTU Center for Genomic Medicine, National Taiwan University , Taipei 100, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000074201:Katanin; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; D048031:JNK Mitogen-Activated Protein Kinases; D000251:Adenosine Triphosphatases; D000074201:Katanin