Abstract

11-Dehydrosinulariolide, an active compound that is isolated from the cultured soft coral Sinularia flexibilis, has been suggested to show anti-tumor biological characteristics according to previous studies. However, its potential effect on small cell lung cancer (SCLC) remains unknown. The present study investigates the underlying mechanism for the treatment of SCLC in vitro and in vivo. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was applied to evaluate cell cycle distribution and apoptosis. The expression of proteins related to the cell cycle and apoptosis was analyzed by Western blot analysis. Additionally, an in vivo study was performed to determine the anti-SCLC effect on an H1688 subcutaneous tumor in a BALB/c nude mouse model. 11-Dehydrosinulariolide inhibited cell growth, triggered G2/M arrest and induced H1688 cell apoptosis in a dose- and time-dependent manner. Additionally, 11-dehydrosinulariolide caused the accumulation of p53 and Bax, accompanied by the activation of DNA damage-inducing kinases, including ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2). Moreover, 11-dehydrosinulariolide increased the activity of caspase-3 and -7, suggesting that caspases are involved in 11-dehydrosinulariolide-induced apoptosis. 11-Dehydrosinulariolide also increased the level of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibited the expression of phosphorylated Akt. In the in vivo study, the intraperitoneal injection of 11-dehydrosinulariolide at a dosage of 10 mg/kg significantly inhibited tumor growth compared with the control treatment. Together, the data indicate that 11-dehydrosinulariolide induces G (2)/M cell cycle arrest and apoptosis through various cellular processes, including the upregulation of p53 and Bax, activation of ATM and Chk2, activation of caspase-3 and -7, and accumulation of PTEN, leading to inhibition of the Akt pathway. These findings suggest that 11-dehydrosinulariolide might serve as a promising chemotherapy drug in the treatment of SCLC.

Details

Title
A Soft Coral-Derived Compound, 11-Dehydrosinulariolide, Induces G2/M Cell Cycle Arrest and Apoptosis in Small Cell Lung Cancer
Author
Yu-Chao, Lin 1 ; Jui-Hsin Su 2 ; Shih-Chao, Lin 3   VIAFID ORCID Logo  ; Chia-Che, Chang 4 ; Te-Chun Hsia 5 ; Yu-Tang, Tung 6   VIAFID ORCID Logo  ; Chi-Chien, Lin 7   VIAFID ORCID Logo 

1  Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan 
2  National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan 
3  National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA 
4  Institute of Biomedical Science, National Chung-Hsing University, Taichung 40227, Taiwan 
5  Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan; Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan 
6  Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110, Taiwan 
7  Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan; Institute of Biomedical Science, National Chung-Hsing University, Taichung 40227, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan 
First page
479
Publication year
2018
Publication date
2018
Publisher
MDPI AG
e-ISSN
16603397
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.3390/md16120479
ProQuest document ID
2582834297
Copyright
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.