Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways.
Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways.
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DOI：
10.1021/jm801344j
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发表时间：
2009-04-09
影响因子：
7.3
通讯作者：
Lee KH
中科院分区：
文献类型：
--
作者：
Lin JC;Yang SC;Hong TM;Yu SL;Shi Q;Wei L;Chen HY;Yang PC;Lee KH
tylophine及其相关天然化合物具有较强的抗肿瘤活性。我们之前发现PBT-1是一种合成的c9取代菲基tylophorine （PBT）衍生物，可以显著抑制各种癌细胞的生长。在本研究中，我们进一步探讨了PBT-1作为抗癌药物的作用机制和潜力。PBT-1剂量依赖性抑制集落形成，诱导细胞周期G2/M阻滞和凋亡。DNA芯片和通路分析显示，PBT-1激活了凋亡通路和丝裂原激活的蛋白激酶信号。相比之下，PBT-1抑制核因子κ b （NF-κB）通路和局灶黏附。我们进一步证实PBT-1抑制Akt活化，通过i -κB激酶-α加速RelA降解，下调NF-κB靶基因表达。RelA和RelB在COX-2启动子区域的相互募集导致转录活性下调。我们得出结论，PBT-1通过灭活Akt和抑制NF-κB信号通路诱导细胞周期G2/M阻滞和凋亡。PBT-1可能是一种很好的抗癌化疗候选药物。
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, 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 downregulated NF-κB target gene expression. The reciprocal recruitment of RelA and RelB on COX-2 promoter region led to downregulation 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.
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