Skip to main content
Log in

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

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a Review. Cancer Res 49:6449–6465

    CAS  PubMed  Google Scholar 

  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 14:191–201

    Article  CAS  PubMed  Google Scholar 

  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 1806:220–229

    CAS  PubMed  Google Scholar 

  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 17:181–189

    Article  CAS  PubMed  Google Scholar 

  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 13:7419–7432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 95:547–552

    Article  CAS  PubMed  Google Scholar 

  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 64:766–771

  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 59:1102–1103

    Article  CAS  PubMed  Google Scholar 

  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 1:2464–2467

    Article  Google Scholar 

  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 392:460–466

    Article  CAS  PubMed  Google Scholar 

  11. Carte B, Faulkner DJ (1981) Polybrominated diphenyl ethers from Dysidea herbacea, Dysidea chlorea and Phyllospongia foliascens. Tetrahedron 37:2335–2339

    Article  CAS  Google Scholar 

  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 58:1384–1391

    Article  CAS  PubMed  Google Scholar 

  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 60:1313–1316

    Article  CAS  PubMed  Google Scholar 

  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 119:1–11

    Article  CAS  Google Scholar 

  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 70:432–435

    Article  CAS  PubMed  Google Scholar 

  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 25:2181–2183

    Article  CAS  PubMed  Google Scholar 

  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 50:453–460

    Article  PubMed  Google Scholar 

  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 19:4006–4020

    Article  PubMed  Google Scholar 

  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 13:6759–6773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 67:472–474

    Article  CAS  PubMed  Google Scholar 

  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 13:657–659

    Article  CAS  PubMed  Google Scholar 

  22. Jin S, DiPaola RS, Mathew R, White E (2007) Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120:379–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee AS (2007) GRP78 Induction in cancer: therapeutic and prognostic implications. Cancer Res 67:3496–3499

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Masayoshi Arai or Motomasa Kobayashi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1

Representative original image of western blotting analysis for Fig. 3b (DOCX 110 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arai, M., Shin, D., Kamiya, K. et al. Marine spongean polybrominated diphenyl ethers, selective growth inhibitors against the cancer cells adapted to glucose starvation, inhibits mitochondrial complex II. J Nat Med 71, 44–49 (2017). https://doi.org/10.1007/s11418-016-1025-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-016-1025-x

Keywords

Navigation