1. Phenanthrene-Based Tylophorine-1 (PBT-1) Inhibits Lung Cancer Cell Growth through the Akt and NF-κB Pathways
- Author
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Tse-Ming Hong, Kuo Hsiung Lee, Shuenn-Chen Yang, Linyi Wei, Sung-Liang Yu, Jau-Chen Lin, Pan-Chyr Yang, Hsuan-Yu Chen, and Qian Shi
- Subjects
G2 Phase ,Programmed cell death ,Lung Neoplasms ,Transcription, Genetic ,Antineoplastic Agents ,Apoptosis ,Article ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Humans ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Focal Adhesions ,Cell growth ,Chemistry ,RELB ,NF-kappa B ,Cell cycle ,Phenanthrenes ,Biochemistry ,Gene Expression Regulation ,Cancer research ,Molecular Medicine ,Signal transduction ,Drug Screening Assays, Antitumor ,Proto-Oncogene Proteins c-akt ,Cell Division ,Signal Transduction - Abstract
Tylophorine and related natural compounds exhibit potent antitumor activities. We previously showed that PBT-1, a synthetic C9-substituted phenanthrene-based tylophorine (PBT) derivative, significantly inhibits growth of various cancer cells. In this study, we further explored the mechanisms and potential of PBT-1 as an anticancer agent. PBT-1 dose-dependently suppressed colony formation and induced cell cycle G2/M arrest and apoptosis. DNA microarray and pathway analysis showed that PBT-1 activated the apoptosis pathway and mitogen-activated protein kinase signaling. In contrast, PBT-1 suppressed the nuclear factor kappaB (NF-kappaB) pathway and focal adhesion. We further confirmed that PBT-1 suppressed Akt activation accelerated RelA degradation via IkappaB kinase-alpha and down-regulated NF-kappaB target gene expression. The reciprocal recruitment of RelA and RelB on COX-2 promoter region led to down-regulation of transcriptional activity. We conclude that PBT-1 induces cell cycle G2/M arrest and apoptosis by inactivating Akt and by inhibiting the NF-kappaB signaling pathway. PBT-1 may be a good drug candidate for anticancer chemotherapy.
- Published
- 2009
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