Limits...
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.

Show MeSH

Related in: MedlinePlus

2-Methoxystypandrone (2-MS) inhibited tumor necrosis factor-α (TNF-α)-induced nuclear factor-κB (NF-κB) signal transduction, phosphorylation of IκB-α and IKK in human tumor cell lines. (a) 2-MS inhibited TNF-α-induced NF-κB regulated luciferase activity. HEK293/NF-κB cells were pretreated with indicated concentrations of 2-MS for 2 h. Luciferase activity was measured following stimulation with TNF-α (2 ng/mL) for 5 h. (b) Effects of 2-MS on cell survival. HEK293/NF-κB cells were treated with indicated concentrations of 2-MS for 7 h. Cell viability was determined by MTT assay. (c) 2-MS inhibited TNF-α-induced phosphorylation of IκB-α. HeLa, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/mL) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IκB-α (Ser32/36) and anti-IκB-α antibodies. Anti-α-Tubulin antibodies were used as a loading control. (d) 2-MS inhibited TNF-α-induced phosphorylation of IKK. H460, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/ml) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IKKα/β (Ser176/180 for IKKα and Ser177/181 for IKKβ) antibodies. Anti-IKK-α antibodies were used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4317813&req=5

fig04: 2-Methoxystypandrone (2-MS) inhibited tumor necrosis factor-α (TNF-α)-induced nuclear factor-κB (NF-κB) signal transduction, phosphorylation of IκB-α and IKK in human tumor cell lines. (a) 2-MS inhibited TNF-α-induced NF-κB regulated luciferase activity. HEK293/NF-κB cells were pretreated with indicated concentrations of 2-MS for 2 h. Luciferase activity was measured following stimulation with TNF-α (2 ng/mL) for 5 h. (b) Effects of 2-MS on cell survival. HEK293/NF-κB cells were treated with indicated concentrations of 2-MS for 7 h. Cell viability was determined by MTT assay. (c) 2-MS inhibited TNF-α-induced phosphorylation of IκB-α. HeLa, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/mL) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IκB-α (Ser32/36) and anti-IκB-α antibodies. Anti-α-Tubulin antibodies were used as a loading control. (d) 2-MS inhibited TNF-α-induced phosphorylation of IKK. H460, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/ml) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IKKα/β (Ser176/180 for IKKα and Ser177/181 for IKKβ) antibodies. Anti-IKK-α antibodies were used as a loading control.

Mentions: We examined the effects of 2-MS on the NF-κB signaling pathway using an NF-κB responsive luciferase reporter gene-transfected HEK293 cell line. We found that 2-MS inhibited TNF-α-induced NF-κB responsive reporter gene activity in a dose-dependent manner, with a half-maximal inhibition dose of 3 μM (Fig. 4a). Parallel to inhibition of NF-κB signaling, 2-MS only slightly decreased the cell number of HEK293 cells (Fig. 4b), suggesting that the inhibition effect of 2-MS on NF-κB signaling was not caused by reduced cell number.


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)

2-Methoxystypandrone (2-MS) inhibited tumor necrosis factor-α (TNF-α)-induced nuclear factor-κB (NF-κB) signal transduction, phosphorylation of IκB-α and IKK in human tumor cell lines. (a) 2-MS inhibited TNF-α-induced NF-κB regulated luciferase activity. HEK293/NF-κB cells were pretreated with indicated concentrations of 2-MS for 2 h. Luciferase activity was measured following stimulation with TNF-α (2 ng/mL) for 5 h. (b) Effects of 2-MS on cell survival. HEK293/NF-κB cells were treated with indicated concentrations of 2-MS for 7 h. Cell viability was determined by MTT assay. (c) 2-MS inhibited TNF-α-induced phosphorylation of IκB-α. HeLa, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/mL) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IκB-α (Ser32/36) and anti-IκB-α antibodies. Anti-α-Tubulin antibodies were used as a loading control. (d) 2-MS inhibited TNF-α-induced phosphorylation of IKK. H460, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/ml) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IKKα/β (Ser176/180 for IKKα and Ser177/181 for IKKβ) antibodies. Anti-IKK-α antibodies were used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: 2-Methoxystypandrone (2-MS) inhibited tumor necrosis factor-α (TNF-α)-induced nuclear factor-κB (NF-κB) signal transduction, phosphorylation of IκB-α and IKK in human tumor cell lines. (a) 2-MS inhibited TNF-α-induced NF-κB regulated luciferase activity. HEK293/NF-κB cells were pretreated with indicated concentrations of 2-MS for 2 h. Luciferase activity was measured following stimulation with TNF-α (2 ng/mL) for 5 h. (b) Effects of 2-MS on cell survival. HEK293/NF-κB cells were treated with indicated concentrations of 2-MS for 7 h. Cell viability was determined by MTT assay. (c) 2-MS inhibited TNF-α-induced phosphorylation of IκB-α. HeLa, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/mL) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IκB-α (Ser32/36) and anti-IκB-α antibodies. Anti-α-Tubulin antibodies were used as a loading control. (d) 2-MS inhibited TNF-α-induced phosphorylation of IKK. H460, DU-145 and A549 cells were incubated with indicated concentrations of 2-MS for 2 h before stimulation with TNF-α (2 ng/ml) for 15 min. Whole cell lysates were subjected to western blot analysis and probed with anti-P-IKKα/β (Ser176/180 for IKKα and Ser177/181 for IKKβ) antibodies. Anti-IKK-α antibodies were used as a loading control.
Mentions: We examined the effects of 2-MS on the NF-κB signaling pathway using an NF-κB responsive luciferase reporter gene-transfected HEK293 cell line. We found that 2-MS inhibited TNF-α-induced NF-κB responsive reporter gene activity in a dose-dependent manner, with a half-maximal inhibition dose of 3 μM (Fig. 4a). Parallel to inhibition of NF-κB signaling, 2-MS only slightly decreased the cell number of HEK293 cells (Fig. 4b), suggesting that the inhibition effect of 2-MS on NF-κB signaling was not caused by reduced cell number.

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