Head and neck cancer cells and xenografts are very sensitive to palytoxin: decrease of c-jun n-terminale kinase-3 expression enhances palytoxin toxicity

• Published in: Molecular cancer Vol. 12; no. 1; p. 12
• Main Authors: Görögh, Tibor, Bèress, László, Quabius, Elgar S, Ambrosch, Petra, Hoffmann, Markus
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.02.2013; BioMed Central; BMC
• Subjects: Acrylamides - administration & dosage; Acrylamides - pharmacology; Adenosine triphosphatase; Analysis; Animal experimentation; Animals; Anti-tumoral effect; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Shape - drug effects; Cell Survival - drug effects; Cnidaria; Drug Synergism; Enzyme inhibitors; Gene expression; Gene Expression - drug effects; H(+)-K(+)-Exchanging ATPase - genetics; H(+)-K(+)-Exchanging ATPase - metabolism; Head and neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - pathology; Humans; Inhibitory Concentration 50; Injections, Intralesional; Injections, Intraperitoneal; JNK3; Kinases; Marine; Marine toxins; Medical research; Mice; Mice, SCID; Mitogen-Activated Protein Kinase 10 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 10 - genetics; Mitogen-Activated Protein Kinase 10 - metabolism; Mitogens; Palythoa caribaeorum; Palytoxin; Protein kinases; Proteins; Pyrazoles - pharmacology; Squamous cell carcinoma; Studies; Toxicity; Tumor Burden - drug effects; Urea - analogs & derivatives; Urea - pharmacology; Xenograft Model Antitumor Assays; Xenografts; Germany
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-12-12

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. 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). 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. 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.