1. Targeting mTOR by CZ415 Inhibits Head and Neck Squamous Cell Carcinoma Cells.
- Author
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Xie J, Li Q, Ding X, and Gao Y
- Subjects
- Adenine analogs & derivatives, Adenine pharmacology, Animals, Apoptosis drug effects, Autophagy drug effects, Beclin-1 antagonists & inhibitors, Beclin-1 genetics, Beclin-1 metabolism, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Survival drug effects, Chloroquine pharmacology, Cyclic S-Oxides therapeutic use, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Mechanistic Target of Rapamycin Complex 1 antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 1 metabolism, Mechanistic Target of Rapamycin Complex 2 antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 2 metabolism, Mice, Mice, Nude, Phenylurea Compounds therapeutic use, Protein Kinase Inhibitors therapeutic use, RNA Interference, RNA, Small Interfering metabolism, Squamous Cell Carcinoma of Head and Neck, TOR Serine-Threonine Kinases antagonists & inhibitors, Transplantation, Heterologous, Tumor Cells, Cultured, Cell Proliferation drug effects, Cyclic S-Oxides toxicity, Phenylurea Compounds toxicity, Protein Kinase Inhibitors toxicity, TOR Serine-Threonine Kinases metabolism
- Abstract
Background/aims: mTOR is an important therapeutic target for human head and neck squamous cell carcinoma (HNSCC). The current study tested the anti-HNSCC cell activity by a mTOR kinase inhibitor CZ415., Methods: HNSCC cells were treated with CZ415. Cell death was tested by lactate dehydrogenase (LDH) assay and MTT assay. Cell proliferation was tested by BrdU ELISA assay and [H3] thymidine incorporation assay, with apoptosis assayed by the TUNEL staining. A Western blotting assay was applied to test autophagy-associated proteins, mTOR and signalings. The nude mice xenograft model was established to study CZ415-mediated anti-tumor activity., Results: In established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells, CZ415 efficiently inhibited cell survival and proliferation. CZ415 blocked mTORC1/2 activation and inhibited ERK in HNSCC cells. CZ415 provoked feedback autophagy activation. Conversely, autophagy inhibitors (3-methyladenine and chloroquine) or Beclin-1 shRNA sensitized CZ415-induced HNSCC cell death. In vivo, CZ415 gavage inhibited SCC-9 tumor growth in nude mice, showing higher efficiency against Beclin-1-silenced tumors., Conclusion: CZ415 inhibits HNSCC cell growth in vitro and in vivo. Inhibition of autophagy can further sensitize CZ415 against HNSCC cells., (© 2018 The Author(s). Published by S. Karger AG, Basel.) more...
- Published
- 2018
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