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2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.

Kuang S, Qi C, Liu J, Sun X, Zhang Q, Sima Z, Liu J, Li W, Yu Q - Cancer Sci. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

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Chemical structure of 2-methoxystypandrone.
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fig01: Chemical structure of 2-methoxystypandrone.

Mentions: We screened an extract library of Chinese medicinal herbs for their inhibitory effect on STAT3 signaling using a STAT3 responsive luciferase reporter gene-transfected HepG2 cell line and found 2-MS (Fig. 1), which inhibited STAT3 activity in both a luciferase assay using the HepG2 cells and a western blotting assay using MDA-MB-231 cells.(21) To confirm the inhibitory effects of 2-MS on the JAK2/STAT3 signaling pathway, we examined its effects on the IL-6-induced phosphorylation/activation of STAT3. 2-MS inhibited both the IL-6-induced and the constitutive phosphorylation/activation of STAT3 in a dose-dependent manner in HeLa cells (Fig. 2a,c). The inhibition was rapid. A 15-min treatment was sufficient to block the activation (Fig. 2b), suggesting direct inhibition of the STAT3 phosphorylation. 2-MS also significantly inhibited the constitutive activation of STAT3 in MCF-7, DU-145 and HepG2 cells (Fig. 2d). Therefore, 2-MS inhibited both the IL-6 induced as well as the constitutive activation of STAT3 in human tumor cells.


2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.

Kuang S, Qi C, Liu J, Sun X, Zhang Q, Sima Z, Liu J, Li W, Yu Q - Cancer Sci. (2014)

Chemical structure of 2-methoxystypandrone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317813&req=5

fig01: Chemical structure of 2-methoxystypandrone.
Mentions: We screened an extract library of Chinese medicinal herbs for their inhibitory effect on STAT3 signaling using a STAT3 responsive luciferase reporter gene-transfected HepG2 cell line and found 2-MS (Fig. 1), which inhibited STAT3 activity in both a luciferase assay using the HepG2 cells and a western blotting assay using MDA-MB-231 cells.(21) To confirm the inhibitory effects of 2-MS on the JAK2/STAT3 signaling pathway, we examined its effects on the IL-6-induced phosphorylation/activation of STAT3. 2-MS inhibited both the IL-6-induced and the constitutive phosphorylation/activation of STAT3 in a dose-dependent manner in HeLa cells (Fig. 2a,c). The inhibition was rapid. A 15-min treatment was sufficient to block the activation (Fig. 2b), suggesting direct inhibition of the STAT3 phosphorylation. 2-MS also significantly inhibited the constitutive activation of STAT3 in MCF-7, DU-145 and HepG2 cells (Fig. 2d). Therefore, 2-MS inhibited both the IL-6 induced as well as the constitutive activation of STAT3 in human tumor cells.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Show MeSH
Related in: MedlinePlus