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Mar. Drugs 2012, 10(8), 1883-1898; doi:10.3390/md10081883
Article

Induction of Apoptosis by 11-Dehydrosinulariolide via Mitochondrial Dysregulation and ER Stress Pathways in Human Melanoma Cells

1,†
, 2,†
, 3
, 2
, 4
, 5
, 6
, 4
, 1
 and 2,*
1 Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung 92842, Taiwan 2 Department of Beauty Science, Meiho University, Pingtung 91202, Taiwan 3 Graduate Institute of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 91202, Taiwan 4 Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80761, Taiwan 5 National Museum of Marine Biology and Aquarium, Pingtung 94446, Taiwan 6 Chemistry Department, National Sun Yat-Sen University, No. 70, Lienhai Rd., Kaohsiung 80424, Taiwan These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 3 July 2012 / Revised: 6 August 2012 / Accepted: 14 August 2012 / Published: 22 August 2012
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Abstract

In this study the isolated compound 11-dehydrosinulariolide from soft coral Sinularia leptoclados possessed anti-proliferative, anti-migratory and apoptosis-inducing activities against A2058 melanoma cells. Anti-tumor effects of 11-dehydrosinulariolide were determined by MTT assay, cell migration assay and flow cytometry. Growth and migration of melanoma cells were dose-dependently inhibited by 2–8 μg/mL 11-dehydrosinulariolide. Flow cytometric data indicated that 11-dehydrosinulariolide induces both early and late apoptosis in melanoma cells. It was found that the apoptosis induced by 11-dehydrosinulariolide is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by loss of mitochondrial membrane potential (∆Ym), release of cytochrome C, activation of caspase-3/-9 and Bax as well as suppression of Bcl-2/Bcl-xL. The cleavage of PARP-1 suggested partial involvement of caspase-independent pathways. Immunoblotting data displayed up-regulations of PERK/eIF2α/ATF4/CHOP and ATF6/CHOP coupling with elevation of ER stress chaperones GRP78, GRP94, calnexin, calreticulin and PDI, implicating the involvement of these factors in ER stress-mediated apoptosis induced by 11-dehydrosinulariolide. The abolishment of apoptotic events after pre-treatment with salubrinal indicated that ER stress-mediated apoptosis is also induced by 11-dehydrosinulariolide against melanoma cells. The data in this study suggest that 11-dehydrosinulariolide potentially induces apoptosis against melanoma cells via mitochondrial dysregulation and ER stress pathways.
Keywords: melanoma; 11-dehydrosinulariolide; mitochondrial dysregulation; ER stress melanoma; 11-dehydrosinulariolide; mitochondrial dysregulation; ER stress
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.

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Su, T.-R.; Tsai, F.-J.; Lin, J.-J.; Huang, H.H.; Chiu, C.-C.; Su, J.-H.; Yang, Y.-T.; Chen, J.-F.; Wong, B.-S.; Wu, Y.-J. Induction of Apoptosis by 11-Dehydrosinulariolide via Mitochondrial Dysregulation and ER Stress Pathways in Human Melanoma Cells. Mar. Drugs 2012, 10, 1883-1898.

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