Abstract
Our previous study demonstrated that the novel indirubin derivative, 5'-nitro-indirubinoxime (5'-NIO), effectively arrested the tumor growth through the inhibition of cell proliferation and the induction of apoptosis. However, the precise molecular mechanisms underlying 5'-NIO-induced antitumor activity remain unclear. Here, we report that 5'-NIO inhibits the proliferation of human KB oral carcinoma cells via the cell cycle arrest in G2/M phase. 5'-NIO reduced the activity of Cdc2/cyclin B complex through the inhibition of the PLK1 expression. Partially, 5'-NIO also arrested cell cycle in G1/S phase via the reduction of CDK4 and cyclin D1/D3 levels by p16 and induction of the level of p21waf1. Using flow cytometry analysis, we showed that 5'-NIO-induced cell cycle arrest is followed by apoptosis. We determined further that 5'-NIO-induced apoptosis is accomplished by the mitochondria-dependent activation of the caspase cascade. Overall, these observations suggest the potential value of 5'-NIO as a candidate for a therapeutic modality for the treatment of oral cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Blotting, Western
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Caspases / metabolism
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Division / drug effects*
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Cell Proliferation / drug effects
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Cyclin D1 / metabolism
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Cyclin D2
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclins / metabolism
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G1 Phase / drug effects
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G2 Phase / drug effects*
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Humans
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Indoles / chemistry
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Indoles / pharmacology*
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KB Cells
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Mouth Neoplasms / metabolism
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Mouth Neoplasms / pathology*
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Oximes / chemistry
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Oximes / pharmacology*
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Polo-Like Kinase 1
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / pharmacology
Substances
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5'-nitroindirubinoxime
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Antineoplastic Agents
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CCND1 protein, human
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CCND2 protein, human
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin D2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Indoles
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Oximes
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Cyclin D1
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Protein Serine-Threonine Kinases
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CDK4 protein, human
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Cyclin-Dependent Kinase 4
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Caspases