Journal of Natural Medicines

, Volume 71, Issue 1, pp 44–49 | Cite as

Marine spongean polybrominated diphenyl ethers, selective growth inhibitors against the cancer cells adapted to glucose starvation, inhibits mitochondrial complex II

  • Masayoshi Arai
  • Dayoung Shin
  • Kentaro Kamiya
  • Ryosuke Ishida
  • Andi Setiawan
  • Naoyuki Kotoku
  • Motomasa Kobayashi
Original Paper


In the course of search for selective growth inhibitors against the cancer cells adapted to nutrient starvation, two polybrominated diphenyl ethers, 3,4,5-tribromo-2-(2′,4′-dibromophenoxy)-phenol (1) and 3,5-dibromo-2-(2′,4′-dibromophenoxy)-phenol (2) were isolated from an Indonesian marine sponge of Dysidea sp. Compounds 1 and 2 showed the anti-proliferative activity against PANC-1 cells under glucose-starved conditions with IC50 values of 2.1 and 3.8 µM, respectively, whereas no growth inhibition was observed up to 30 µM in the general culture conditions. The further mechanistic analysis indicated that compound 1 might act mainly by inhibiting complex II in the mitochondrial electron transport chain.


Polybrominated diphenyl ether Marine sponge Cancer Glucose starvation Mitochondrial electron transport chain 



The human pancreatic carcinoma cell line, PANC-1 (RCB2095), was provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan. The authors are grateful to Dr. Nicole J. de Voogd, National Museum of Natural History, the Netherlands for identifying the sponge specimen. This study was financially supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and development (AMED), the Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (JSPS, 15H03114, 26242074, and 26305002), and the Grant-in-Aid for Scientific Research on Innovative Areas from MEXT (23102005).

Supplementary material

11418_2016_1025_MOESM1_ESM.docx (109 kb)
Fig. S1 Representative original image of western blotting analysis for Fig. 3b (DOCX 110 kb)


  1. 1.
    Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a Review. Cancer Res 49:6449–6465PubMedGoogle Scholar
  2. 2.
    Rohwer N, Cramer T (2011) Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat 14:191–201CrossRefPubMedGoogle Scholar
  3. 3.
    Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J (2010) Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta 1806:220–229PubMedGoogle Scholar
  4. 4.
    Arai M, Kawachi T, Kotoku N, Nakata C, Kamada H, Tsunoda S, Tsutsumi Y, Endo H, Inoue M, Sato H, Kobayashi M (2016) Furospinosulin-1, marine spongean furanosesterterpene, suppresses the growth of hypoxia-adapted cancer cells by binding to transcriptional regulators p54nrb and LEDGF/p75. ChemBioChem 17:181–189CrossRefPubMedGoogle Scholar
  5. 5.
    Sumii Y, Kotoku N, Fukuda A, Kawachi T, Arai M, Kobayashi M (2015) Structure-activity relationship and in vivo anti-tumor evaluations of dictyoceratin-A and -C, hypoxia-selective growth inhibitors from marine sponge. Mar Drugs 13:7419–7432CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lu J, Kunimoto S, Yamazaki Y, Kaminishi M, Esumi H (2004) Kigamicin D, a novel anticancer agent based on a new anti-austerity strategy targeting cancer cells’ tolerance to nutrient starvation. Cancer Sci 95:547–552CrossRefPubMedGoogle Scholar
  7. 7.
    Arai M, Kamiya K, Shin D, Matsumoto H, Hisa T, Setiawan A, Kotoku N, Kobayashi M (2016) N-Methylniphatyne A, a new 3-alkylpyridine alkaloid as an inhibitor of the cancer cells adapted to nutrient starvation, from an Indonesian marine sponge of Xestospongia sp. Chem Pharm Bull 64:766–771Google Scholar
  8. 8.
    Fu X, Schmitz FJ (1996) New brominated diphenyl ether from an unidentified species of Dysidea sponge. 13C NMR Data for some brominated diphenyl ethers. J Nat Prod 59:1102–1103CrossRefPubMedGoogle Scholar
  9. 9.
    Capon R, Ghisalberti EL, Jefferies PR, Skelton BW, White AH (1981) Structural studies of halogenated diphenyl ethers from a marine sponge. J Chem Soc Perkin Trans 1:2464–2467CrossRefGoogle Scholar
  10. 10.
    Momose I, Ohba S, Tatsuda D, Kawada M, Masuda T, Tsujiuchi G, Yamori T, Esumi H, Ikeda D (2010) Mitochondrial inhibitors show preferential cytotoxicity to human pancreatic cancer PANC-1 cells under glucose-deprived conditions. Biochem Biophys Res Commun 392:460–466CrossRefPubMedGoogle Scholar
  11. 11.
    Carte B, Faulkner DJ (1981) Polybrominated diphenyl ethers from Dysidea herbacea, Dysidea chlorea and Phyllospongia foliascens. Tetrahedron 37:2335–2339CrossRefGoogle Scholar
  12. 12.
    Fu X, Schmitz FJ, Govindan M, Abbas SA, Hanson KM, Horton PA, Crews P, Laney M, Schatzman RC (1995) Enzyme inhibitors: new and known polybrominated phenols and diphenyl ethers from four Indo-Pacific Dysidea sponges. J Nat Prod 58:1384–1391CrossRefPubMedGoogle Scholar
  13. 13.
    Handayani D, Edrada RA, Proksch P, Wray V, Witte L, van Soest RWM, Kunzmann A, Soedarsono (1997) Four new bioactive polybrominated diphenyl ethers of the sponge Dysidea herbacea from West Sumatra, Indonesia. J Nat Prod 60:1313–1316CrossRefPubMedGoogle Scholar
  14. 14.
    Unson MD, Holland ND, Faulkner DJ (1994) A brominated secondary metabolite synthesized by the cyanobacterial symbiont of a marine sponge and accumulation of the crystalline metabolite in the sponge tissue. Mar Biol 119:1–11CrossRefGoogle Scholar
  15. 15.
    Hanif N, Tanaka J, Setiawan A, Trianto A, de Voogd NJ, Murni A, Tanaka C, Higa T (2007) Polybrominated diphenyl ethers from the Indonesian sponge Lamellodysidea herbacea. J Nat Prod 70:432–435CrossRefPubMedGoogle Scholar
  16. 16.
    Sun S, Canning CB, Bhargava K, Sun X, Zhu W, Zhou N, Zhang Y, Zhou K (2015) Polybrominated diphenyl ethers with potent and broad spectrum antimicrobial activity from the marine sponge Dysidea. Bioorg Med Chem Lett 25:2181–2183CrossRefPubMedGoogle Scholar
  17. 17.
    Sionov E, Roth D, Sandovsky-Losica H, Kashman Y, Rudi A, Chill L, Berdicevsky I, Segal E (2005) Antifungal effect and possible mode of activity of a compound from the marine sponge Dysidea herbacea. J Infect 50:453–460CrossRefPubMedGoogle Scholar
  18. 18.
    Salam KA, Furuta A, Noda N, Tsuneda S, Sekiguchi Y, Yamashita A, Moriishi K, Nakakoshi M, Tani H, Roy SR, Tanaka J, Tsubuki M, Akimitsu N (2014) PBDE: structure-activity studies for the inhibition of hepatitis C virus NS3 helicase. Molecules 19:4006–4020CrossRefPubMedGoogle Scholar
  19. 19.
    Yamashita A, Fujimoto Y, Tamaki M, Setiawan A, Tanaka T, Okuyama-Dobashi K, Kasai H, Watashi K, Wakita T, Toyama M, Baba M, de Voogd NJ, Maekawa S, Enomoto N, Tanaka J, Moriishi K (2015) Identification of antiviral agents targeting hepatitis B virus promoter from extracts of Indonesian marine organisms by a novel cell-based screening assay. Mar Drugs 13:6759–6773CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Liu H, Namikoshi M, Meguro S, Nagai H, Kobayashi H, Yao X (2004) Isolation and characterization of polybrominated diphenyl ethers as inhibitors of microtubule assembly from the marine sponge Phyllospongia dendyi collected at Palau. J Nat Prod 67:472–474CrossRefPubMedGoogle Scholar
  21. 21.
    Xu Y, Johnson RK, Hecht SM (2005) Polybrominated diphenyl ethers from a sponge of the Dysidea genus that inhibit Tie2 kinase. Bioorg Med Chem 13:657–659CrossRefPubMedGoogle Scholar
  22. 22.
    Jin S, DiPaola RS, Mathew R, White E (2007) Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120:379–383CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lee AS (2007) GRP78 Induction in cancer: therapeutic and prognostic implications. Cancer Res 67:3496–3499CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan 2016

Authors and Affiliations

  • Masayoshi Arai
    • 1
  • Dayoung Shin
    • 1
  • Kentaro Kamiya
    • 1
  • Ryosuke Ishida
    • 1
  • Andi Setiawan
    • 2
  • Naoyuki Kotoku
    • 1
  • Motomasa Kobayashi
    • 1
  1. 1.Graduate School of Pharmaceutical SciencesOsaka UniversitySuitaJapan
  2. 2.Department of Chemistry, Faculty of ScienceLampung UniversityBandar LampungIndonesia

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