title: NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells.
abstract: Disrupting lung tumor growth via histone deacetylases (HDACs) inhibition is a strategy for cancer therapy or prevention. Targeting HDAC6 may disturb the maturation of heat shock protein 90 (Hsp90) mediated cell cycle regulation. In this study, we demonstrated the effects of semisynthesized NBM-T-BBX-OS01 (TBBX) from osthole on HDAC6-mediated growth arrest in lung cancer cells. The results exhibited that the anti-proliferative activity of TBBX in numerous lung cancer cells was more potent than suberoylanilide hydroxamic acid (SAHA), a clinically approved pan-HDAC inhibitor, and the growth inhibitory effect has been mediated through G1 growth arrest. Furthermore, the protein levels of cyclin D1, CDK2 and CDK4 were reduced while cyclin E and CDK inhibitor, p21Waf1/Cip1, were up-regulated in TBBX-treated H1299 cells. The results also displayed that TBBX inhibited HDAC6 activity via down-regulation HDAC6 protein expression. TBBX induced Hsp90 hyper-acetylation and led to the disruption of cyclin D1/Hsp90 and CDK4/Hsp90 association following the degradation of cyclin D1 and CDK4 proteins through proteasome. Ectopic expression of HDAC6 rescued TBBX-induced G1 arrest in H1299 cells. Conclusively, the data suggested that TBBX induced G1 growth arrest may mediate HDAC6-caused Hsp90 hyper-acetylation and consequently increased the degradation of cyclin D1 and CDK4.
authors.affiliation: Division of Hematology and Oncology, Tao-Yuan General Hospital, Ministry of Health and Welfare, Taoyuan City 33004, Taiwan. jihtungpai@gmail.com.
authors.forename: Jih-Tung
authors.initials: JT
authors.lastname: Pai
authors.affiliation: Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 24205, Taiwan. sandy0805w@hotmail.com.
authors.forename: Chia-Yun
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan. d94447003@gmail.com.
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.affiliation: Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 24205, Taiwan. j06103@hotmail.com.
authors.forename: Sheng-Yung
authors.initials: SY
authors.lastname: Yu
authors.affiliation: NatureWise Biotech and Medicals Corporation, Taipei 11559, Taiwan. naturewisecyh@gmail.com.
authors.forename: Chung-Yang
authors.initials: CY
authors.lastname: Huang
authors.affiliation: NatureWise Biotech and Medicals Corporation, Taipei 11559, Taiwan. alex_chen@gnt.com.tw.
authors.forename: Chia-Nan
authors.initials: CN
authors.lastname: Chen
authors.affiliation: Division of Drug and New Technology Product, Food and Drug Administration, Ministry of Health and Welfare, Executive Yuan, Taipei 11516, Taiwan. cedar@fda.gov.tw.
authors.forename: Chiung-Ho
authors.initials: CH
authors.lastname: Liao
authors.affiliation: Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 24205, Taiwan. 078670@mail.fju.edu.tw.
authors.forename: Meng-Shih
authors.initials: MS
authors.lastname: Weng
mesh_terms: D000107:Acetylation / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D003374:Coumarins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C046627:osthol