Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways.
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.
Lin
Jau-Chen
JC
Institute of Biomedical Sciences and Institute of Statistical Science, Academia Sinica, NanKang, Taipei, Taiwan.
Yang
Shuenn-Chen
SC
Hong
Tse-Ming
TM
Yu
Sung-Liang
SL
Shi
Qian
Q
Wei
Linyi
L
Chen
Hsuan-Yu
HY
Yang
Pan-Chyr
PC
Lee
Kuo-Hsiung
KH
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D022001:Focal Adhesions / Q000187:drug effects; D016195:G2 Phase; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; C540181:N-(2,3-methylenedioxy-6-methoxyphenanthr-9-ylmethyl)-4-piperidinem ethanol; D016328:NF-kappa B; D010616:Phenanthrenes; D051057:Proto-Oncogene Proteins c-akt