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Mar. Drugs 2018, 16(6), 204; https://doi.org/10.3390/md16060204

Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90

1
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan
2
Division of Urology, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
3
Division of Urology, Department of Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 813, Taiwan
4
Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
5
Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
6
Department of Urology, Sinying Hospital, Ministry of Health and Welfare, Tainan 730, Taiwan
7
Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 115, Egypt
8
Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 114, Egypt
9
Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan
10
National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan
11
Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, 70 Lien-Hai Road, Kaohsiung 804, Taiwan
12
Doctoral Degree Program in Marine Biotechnology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan
13
Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan
14
Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan
15
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 14 May 2018 / Revised: 31 May 2018 / Accepted: 9 June 2018 / Published: 10 June 2018
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Abstract

Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1–68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9–99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent. View Full-Text
Keywords: antitumor; apoptosis; autophagy; ER stress; heteronemin; Hsp90; topoisomerase II catalytic inhibitor antitumor; apoptosis; autophagy; ER stress; heteronemin; Hsp90; topoisomerase II catalytic inhibitor
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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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Lee, M.-G.; Liu, Y.-C.; Lee, Y.-L.; El-Shazly, M.; Lai, K.-H.; Shih, S.-P.; Ke, S.-C.; Hong, M.-C.; Du, Y.-C.; Yang, J.-C.; Sung, P.-J.; Wen, Z.-H.; Lu, M.-C. Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90. Mar. Drugs 2018, 16, 204.

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