Abstract
Background and aim:
Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma.
Materials and methods:
The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor.
Results:
The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma.
Conclusions:
Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / administration & dosage
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / therapeutic use
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Animals
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Carcinoma, Squamous Cell / blood supply
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cells, Cultured
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Female
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Head and Neck Neoplasms / blood supply
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Head and Neck Neoplasms / drug therapy
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Isoxazoles / administration & dosage
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Isoxazoles / pharmacology
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Isoxazoles / therapeutic use*
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Mice
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Mice, Nude
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Molecular Targeted Therapy
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Mouth Neoplasms / blood supply
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Mouth Neoplasms / drug therapy*
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Mouth Neoplasms / metabolism
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Mouth Neoplasms / pathology
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Random Allocation
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Resorcinols / administration & dosage
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Resorcinols / pharmacology
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Resorcinols / therapeutic use*
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Sirolimus / administration & dosage
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Sirolimus / analogs & derivatives*
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Sirolimus / pharmacology
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Sirolimus / therapeutic use
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Squamous Cell Carcinoma of Head and Neck
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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Xenograft Model Antitumor Assays
Substances
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5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
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Angiogenesis Inhibitors
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HSP90 Heat-Shock Proteins
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Isoxazoles
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Resorcinols
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temsirolimus
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TOR Serine-Threonine Kinases
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Sirolimus