title: Head and neck cancer cells and xenografts are very sensitive to palytoxin: decrease of c-jun n-terminale kinase-3 expression enhances palytoxin toxicity.
abstract: OBJECTIVE
  Palytoxin (PTX), a marine toxin isolated from the Cnidaria (zooanthid) Palythoa caribaeorum is one of the most potent non-protein substances known. It is a very complex molecule that presents both lipophilic and hydrophilic areas. The effect of PTX was investigated in a series of experiments conducted in head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.
  
  
  METHODS
  Cell viability, and gene expression of the sodium/potassium-transporting ATPase subumit alpha1 (ATP1AL1) and GAPDH were analyzed in HNSCC cells and normal epithelial cells after treatment with PTX using cytotoxicity-, clonogenic-, and enzyme inhibitor assays as well as RT-PCR and Northern Blotting. For xenograft experiments severe combined immunodeficient (SCID) mice were used to analyze tumor regression. The data were statistically analyzed using One-Way Annova (SPSS vs20).
  
  
  RESULTS
  Significant toxic effects were observed in tumor cells treated with PTX (LD50 of 1.5 to 3.5 ng/ml) in contrast to normal cells. In tumor cells PTX affected both the release of LDH and the expression of the sodium/potassium-transporting ATPase subunit alpha1 gene suggesting loss of cellular integrity, primarily of the plasma membrane. Furthermore, strong repression of the c-Jun N-terminal kinase 3 (JNK3) mRNA expression was found in carcinoma cells which correlated with enhanced toxicity of PTX suggesting an essential role of the mitogen activated protein kinase (MAPK)/JNK signalling cascades pathway in the mechanisms of HNSCC cell resistance to PTX. In mice inoculated with carcinoma cells, injections of PTX into the xenografted tumors resulted within 24 days in extensive tumor destruction in 75% of the treated animals (LD50 of 68 ng/kg to 83 ng/kg) while no tumor regression occurred in control animals.
  
  
  CONCLUSIONS
  These results clearly provide evidence that PTX possesses preferential toxicity for head and neck carcinoma cells and therefore it is worth further studying its impact which may extend our knowledge of the biology of head and neck cancer.
authors: Department of Otorhinolaryngology- Head and Neck Surgery, Section of Experimental Oncology, University of Kiel Schleswig-Holstein, Kiel, 24105, Germany. gorogh@hno.uni-kiel.de
authors: Tibor
authors: T
authors: Görögh
authors: László
authors: L
authors: Bèress
authors: Elgar S
authors: ES
authors: Quabius
authors: Petra
authors: P
authors: Ambrosch
authors: Markus
authors: M
authors: Hoffmann
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003064:Cnidarian Venoms; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D051379:Mice; D016513:Mice, SCID; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000095702:Polyether Toxins
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D003064:Cnidarian Venoms; D017506:H(+)-K(+)-Exchanging ATPase; D048057:Mitogen-Activated Protein Kinase 10; D011720:Pyrazoles; D014508:Urea; C088641:ATP12A protein, human; C010272:palytoxin; D000095702:Polyether Toxins