Diarylquinoline compounds induce autophagy-associated cell death by inhibiting the Akt pathway and increasing reactive oxygen species in human nasopharyngeal carcinoma cells.

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.

• Authors: Yuchen Cai, Zhihui Wan, Tiemin Sun, Yanxia Shi, Yueli Sun, Peiyu Huang, Su Li, Wenqi Jiang
• Journal: Oncology reports (Oncol Rep) Vol. 29 Issue 3 Pg. 983-92 (Mar 2013) ISSN: 1791-2431 [Electronic] Greece
• PMID: 23291974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Diarylquinolines
• MAP1LC3A protein, human
• Membrane Proteins
• Microtubule-Associated Proteins
• N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methl)-N-(3,4-dichlorophenyl)-3-(4-methylpiperazin-1-yl)propanamide
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects)
• Beclin-1
• Carcinoma
• Cell Line, Tumor
• Diarylquinolines (chemical synthesis, pharmacology)
• Drug Screening Assays, Antitumor
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Inhibitory Concentration 50
• Membrane Potential, Mitochondrial (drug effects)
• Membrane Proteins (metabolism)
• Microtubule-Associated Proteins (metabolism)
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction