2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.
Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) or the nuclear factor-κB (NF-κB) pathway occurs frequently in cancer cells and contributes to oncogenesis. The activation of Janus kinase 2 (JAK2) and IκB kinase (IKK) are key events in STAT3 and NF-κB signaling, respectively. We have identified 2-methoxystypandrone (2-MS) from a traditional Chinese medicinal herb Polygonum cuspidatum as a novel dual inhibitor of JAK2 and IKK. 2-MS inhibits both interleukin-6-induced and constitutively-activated STAT3, as well as tumor necrosis factor-α-induced NF-κB activation. 2-MS specifically inhibits JAK and IKKβ kinase activities but has little effect on activities of other kinases tested. The inhibitory effects of 2-MS on STAT3 and NF-κB signaling can be eliminated by DTT or glutathione and can last for 4 h after a pulse treatment. Furthermore, 2-MS inhibits growth and induces death of tumor cells, particularly those with constitutively-activated STAT3 or NF-κB signaling. We propose that the natural compound 2-MS, as a potent dual inhibitor of STAT3 and NF-κB pathways, is a promising anticancer drug candidate.
Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Shan
S
Kuang
Chunting
C
Qi
Jiawei
J
Liu
Xiaoxiao
X
Sun
Qing
Q
Zhang
Zhenhua
Z
Sima
Jingli
J
Liu
Wuguo
W
Li
Qiang
Q
Yu
D017209:Apoptosis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis; D053614:Janus Kinase 2 / Q000096:biosynthesis* / Q000235:genetics; D008516:Medicine, Chinese Traditional; D016328:NF-kappa B / Q000235:genetics*; D009285:Naphthoquinones / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C447630:2-Methoxystypandrone; D015850:Interleukin-6; D016328:NF-kappa B; D009285:Naphthoquinones; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D053614:Janus Kinase 2; D051550:I-kappa B Kinase
2-Methoxystypandrone; Janus kinase 2/signal transducer and activator of transcription 3 pathway; anticancer drug; natural compound; tumor necrosis factor-α/nuclear factor-κB pathway