Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 7, Pages 1903-1911Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm801344j
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Funding
- National Research Program for Genomic Medicine [DOH97-TD-G-111-018]
- National Cancer Institute, NIH [17625]
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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-kappa B) pathway and focal adhesion. We further confirmed that PBT-1 suppressed Akt activation accelerated RelA degradation via I kappa B kinase-alpha and down-regulated NF-kappa B target gene expression. The reciprocal recruitment of RelA and Re1A 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-kappa B signaling pathway. PBT-1 may be a good drug candidate for anticancer chemotherapy.
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