Hexa-, hepta- and nonaprenylhydroquinones isolated from marine sponges Sarcotragus muscarum and Ircinia fasciculata inhibit NF-kappaB signalling in H4IIE cells.
OBJECTIVE
Marine organisms have proven to be a rich source of potent pharmacologically active compounds. Three polyprenyl-1,4-hydroquinone derivates (hexaprenyl-1,4-hydroquinone, heptaprenyl-1,4-hydroquinone and nonaprenyl-1,4-hydroquinone) were isolated from the Zoobenthos-inhabiting sponges Sarcotragus muscarum and Ircinia fasciculata from the Eastern Mediterranean Sea (phylum: Porifera; class: Demospongiae).


METHODS
Hexa-, hepta- and nonaprenylhydroquinone were identified by (1)H-NMR, H,H-COSY, heteronuclear multiple bond correlation, FAB-MS and UV spectroscopy. The effects of the compounds on cell viability was determined using the MTT assay; anti-oxidative potential was measured using the Trolox equivalent antioxidative capacity assay. Inhibition of nuclear factor-kappaB activity was detected by secreted alkaline phosphatase assay. Activity against an array of protein kinases was determined in 96-well FlashPlates.


RESULTS
All compounds had prominent antioxidative activity, comparable to that of the synthetic vitamin E derivate Trolox. Hexaprenylhydroquinone showed the greatest cytotoxicity in H4IIE hepatoma cells (EC50 2.5 muM). All three compounds inhibited NF-kappaB signalling in this cell line, with heptaprenylhydroquinone being the most active. Screening of 23 kinases involved in signal transduction pathways (cell proliferation, survival, angiogenesis and metastasis) showed that hexaprenylhydroquinone and heptaprenylhydroquinone inhibited the activity of the epidermal growth factor receptor (IC50 1.6 and 1.4 mug/ml, respectively), and heptaprenylhydroquinone also inhibited the activity of other kinases (Src tyrosine kinase, vascular endothelial growth factor receptor 3 and insulin-like growth factor 1 receptor).


CONCLUSIONS
The prenylated hydroquinones isolated from the marine sponges S. muscarum and I. fasciculata showed cytotoxic and antioxidative activities and inhibited NF-kappaB signalling in H4IIE hepatoma cells and protein kinases. These findings may result in the generation of new lead substances in cancer therapy.
Wätjen
Wim
W
Institute of Toxicology, Heinrich-Heine-Universität, Düsseldorf, Germany. wim.waetjen@uni-duesseldorf.de
Putz
Annika
A
Chovolou
Yvonni
Y
Kampkötter
Andreas
A
Totzke
Frank
F
Kubbutat
Michael H G
MH
Proksch
Peter
P
Konuklugil
Belma
B
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006873:Hydroquinones / Q000302:isolation & purification / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011161:Porifera / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000970:Antineoplastic Agents; D000975:Antioxidants; D006873:Hydroquinones; D016328:NF-kappa B; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases