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Molecules 2015, 20(5), 8000-8019; doi:10.3390/molecules20058000

NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells

1
Division of Hematology and Oncology, Tao-Yuan General Hospital, Ministry of Health and Welfare, Taoyuan City 33004, Taiwan
2
Department of Nutritional Science, Fu Jen Catholic University, New Taipei City 24205, Taiwan
3
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
4
NatureWise Biotech and Medicals Corporation, Taipei 11559, Taiwan
5
Division of Drug and New Technology Product, Food and Drug Administration, Ministry of Health and Welfare, Executive Yuan, Taipei 11516, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 24 March 2015 / Revised: 27 April 2015 / Accepted: 28 April 2015 / Published: 4 May 2015
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1070 KB, uploaded 4 May 2015]   |  

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. View Full-Text
Keywords: histone deacetylase; heat shock protein 90; cell cycle arrest; NBM-T-BBX-OS01 (TBBX); suberoylanilide hydroxamic acid (SAHA); lung cancer histone deacetylase; heat shock protein 90; cell cycle arrest; NBM-T-BBX-OS01 (TBBX); suberoylanilide hydroxamic acid (SAHA); lung cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Pai, J.-T.; Hsu, C.-Y.; Hua, K.-T.; Yu, S.-Y.; Huang, C.-Y.; Chen, C.-N.; Liao, C.-H.; Weng, M.-S. NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells. Molecules 2015, 20, 8000-8019.

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