Abstract
Agents that interfere with mitotic progression by disturbing microtubule dynamics are commonly used for cancer treatment. Previously, a series of aroylquinolone regioisomers as novel microtubule inhibitors were discovered. One of these new compounds, MPT0B214 inhibited tubulin polymerization through strongly binding to the tubulin's colchicine-binding site and had cytotoxic activity in a variety of human tumor cell lines. After treatment with MPT0B214, KB cells were arrested in the G2-M phase before cell death occurred, which were associated with upregulation of cyclin B1, dephosphorylation of Cdc2, phosphorylation of Cdc25C and elevated expression of the mitotic marker MPM-2. Furthermore, the compound induced apoptotic cell death through mitochondria/caspase 9-dependent pathway. Notably, several KB-derived multidrug-resistant cancer cell lines were also sensitive to MPT0B214 treatment. These findings showed that MPT0B214 is a potential compound in the treatment of various malignancies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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Aminoquinolines / chemistry
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Aminoquinolines / pharmacology*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Binding Sites
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Colchicine / metabolism
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Cytochromes c / metabolism
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Drug Resistance, Neoplasm / genetics
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Gene Expression
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Inhibitory Concentration 50
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Membrane Potential, Mitochondrial / drug effects
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Microtubules / metabolism*
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Mitochondria / drug effects*
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Mitochondria / metabolism*
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Phosphorylation / drug effects
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Protein Binding
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Protein Multimerization / drug effects
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction / drug effects*
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Tubulin / chemistry
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Tubulin / metabolism
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Tubulin Modulators / chemistry
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Tubulin Modulators / pharmacology*
Substances
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5-amino-6-methoxy-2-(3',4',5'-trimethoxybenzoyl)quinoline
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ATP Binding Cassette Transporter, Subfamily B
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Aminoquinolines
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Antineoplastic Agents
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Cell Cycle Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tubulin
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Tubulin Modulators
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Cytochromes c
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Colchicine
Grants and funding
This work was supported by grants from National Science Council (NSC-101-2325-B-400-007), Department of Health (DOH101-TD-C-111-004), and National Health Research Institutes (CA-101-PP-22), Taiwan, ROC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.