Phenanthrene-Based Tylophorine-1 (PBT-1) Inhibits Lung Cancer Cell Growth through the Akt and NF-κB Pathways

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• 作者：Jau-Chen Lin^† ; ^# ; Shuenn-Chen Yang^† ; ^# ; Tse-Ming Hong^‡ ; ; Sung-Liang Yu^‡ ; ; Qian Shi^§ ; ; Linyi Wei^&
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 9, 2009
• 年：2009
• 卷：52
• 期：7
• 页码：1903-1911
• 全文大小：413K
• 年卷期：v.52,no.7(April 9, 2009)
• ISSN：1520-4804

文摘

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-κB) pathway and focal adhesion. We further confirmed that PBT-1 suppressed Akt activation accelerated RelA degradation via IκB kinase-α and down-regulated NF-κB 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-κB signaling pathway. PBT-1 may be a good drug candidate for anticancer chemotherapy.