Abstract
Diarylquinoline compounds are newly synthesized derivatives of the new anti-tuberculosis drug, TMC207. In this study, nine diarylquinoline compounds were screened for cytotoxic activity against human tumor cells, and their mechanisms of action were investigated. Among the nine compounds, STM-57 [N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methl)-N-(3,4-dichlorophenyl)-3-(4 -methylpiperazin-1-yl)propanamide] showed potent cytotoxic activity. STM-57 induced caspase-independent cell death in the human nasopharyngeal carcinoma cell line, CNE-2. Further investigation showed that STM-57 induced autophagy, as determined with the increased expression of green fluorescent protein-light chain 3 (GFP-LC3) and increased LC3-II levels. STM-57 inhibited the phosphorylation of Akt and the mammalian target of rapamycin (mTOR) in CNE-2 cells. The intracellular calcium concentration and reactive oxygen species levels were increased in CNE-2 cells following treatment with STM-57, whereas the mitochondrial transmembrane potential (ΔΨm) and ATP concentrations were decreased.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / drug effects*
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Beclin-1
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Carcinoma
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Cell Line, Tumor
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Diarylquinolines / chemical synthesis
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Diarylquinolines / pharmacology*
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Drug Screening Assays, Antitumor
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G1 Phase Cell Cycle Checkpoints / 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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Membrane Proteins / metabolism
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Microtubule-Associated Proteins / metabolism
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Nasopharyngeal Carcinoma
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Nasopharyngeal Neoplasms
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Reactive Oxygen Species / metabolism*
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Signal Transduction
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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Diarylquinolines
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MAP1LC3A protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methl)-N-(3,4-dichlorophenyl)-3-(4-methylpiperazin-1-yl)propanamide
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Proto-Oncogene Proteins c-bcl-2
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Reactive Oxygen Species
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Proto-Oncogene Proteins c-akt