Abstract
Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abietanes / metabolism
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Abietanes / pharmacology*
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Animals
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Aurora Kinase B / antagonists & inhibitors*
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Aurora Kinase B / genetics
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Aurora Kinase B / metabolism
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Binding Sites
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Catalytic Domain
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / radiation effects
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G2 Phase Cell Cycle Checkpoints / drug effects
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G2 Phase Cell Cycle Checkpoints / radiation effects
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Humans
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Mice
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Mice, Nude
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Molecular Docking Simulation
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Mouth Neoplasms / enzymology
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Mouth Neoplasms / genetics
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Mouth Neoplasms / pathology
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Mouth Neoplasms / radiotherapy*
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Protein Binding
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Radiation Tolerance / drug effects*
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Radiation-Sensitizing Agents / metabolism
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Radiation-Sensitizing Agents / pharmacology*
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Squamous Cell Carcinoma of Head and Neck / enzymology
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Squamous Cell Carcinoma of Head and Neck / genetics
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Squamous Cell Carcinoma of Head and Neck / pathology
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Squamous Cell Carcinoma of Head and Neck / radiotherapy*
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Tumor Burden / drug effects
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Tumor Burden / radiation effects
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Xenograft Model Antitumor Assays
Substances
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Abietanes
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Protein Kinase Inhibitors
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Radiation-Sensitizing Agents
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tanshinone
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AURKB protein, human
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Aurora Kinase B