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

Görögh T, Bèress L, Quabius ES, Ambrosch P, Hoffmann M - Mol. Cancer (2013)

Bottom Line: 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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Otorhinolaryngology- Head and Neck Surgery, Section of Experimental Oncology, University of Kiel Schleswig-Holstein, Kiel, 24105, Germany. gorogh@hno.uni-kiel.de

ABSTRACT

Objectives: 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.

Materials and 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.

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ATP1AL1- and GAPDH-gene expressions in UKHN-2 cells. (A and B) Expression profiles of the ATP1AL1- and GAPDH-genes during exposure of the tumor cells to PTX of different concentrations. (C) Densitometric measurements of the relative gene expression detected by RT-PCR. Data represent mean ± SDs of triplicate measurements.
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Figure 4: ATP1AL1- and GAPDH-gene expressions in UKHN-2 cells. (A and B) Expression profiles of the ATP1AL1- and GAPDH-genes during exposure of the tumor cells to PTX of different concentrations. (C) Densitometric measurements of the relative gene expression detected by RT-PCR. Data represent mean ± SDs of triplicate measurements.

Mentions: PTX was applied in vitro to tumor cells, to study the effect of PTX on Na+, K+ ATPase by measuring ATP1AL1 gene expression. In three independent tumor cell cultures we observed that PTX (0.3 ng/ml) had no effect on ATP1AL1 gene expression. However 0.6 ng/ml PTX led to down-regulation of the gene (Figure4). Interestingly, down-regulation of ATP1AL1 gene expression did not progress when higher PTX concentrations were used. Quite the contrary occurred: ATP1AL1 gene expression increased, reaching a maximum at 1.5 ng/ml PTX. Additional increases of PTX concentrations in turn caused abrupt decrease in ATP1AL1 gene expression. Similar effects of PTX were seen when analysing GAPDH gene expression (Figure4).


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

Görögh T, Bèress L, Quabius ES, Ambrosch P, Hoffmann M - Mol. Cancer (2013)

ATP1AL1- and GAPDH-gene expressions in UKHN-2 cells. (A and B) Expression profiles of the ATP1AL1- and GAPDH-genes during exposure of the tumor cells to PTX of different concentrations. (C) Densitometric measurements of the relative gene expression detected by RT-PCR. Data represent mean ± SDs of triplicate measurements.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585753&req=5

Figure 4: ATP1AL1- and GAPDH-gene expressions in UKHN-2 cells. (A and B) Expression profiles of the ATP1AL1- and GAPDH-genes during exposure of the tumor cells to PTX of different concentrations. (C) Densitometric measurements of the relative gene expression detected by RT-PCR. Data represent mean ± SDs of triplicate measurements.
Mentions: PTX was applied in vitro to tumor cells, to study the effect of PTX on Na+, K+ ATPase by measuring ATP1AL1 gene expression. In three independent tumor cell cultures we observed that PTX (0.3 ng/ml) had no effect on ATP1AL1 gene expression. However 0.6 ng/ml PTX led to down-regulation of the gene (Figure4). Interestingly, down-regulation of ATP1AL1 gene expression did not progress when higher PTX concentrations were used. Quite the contrary occurred: ATP1AL1 gene expression increased, reaching a maximum at 1.5 ng/ml PTX. Additional increases of PTX concentrations in turn caused abrupt decrease in ATP1AL1 gene expression. Similar effects of PTX were seen when analysing GAPDH gene expression (Figure4).

Bottom Line: 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 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Otorhinolaryngology- Head and Neck Surgery, Section of Experimental Oncology, University of Kiel Schleswig-Holstein, Kiel, 24105, Germany. gorogh@hno.uni-kiel.de

ABSTRACT

Objectives: 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.

Materials and 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.

Show MeSH
Related in: MedlinePlus