2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.
Bottom Line: 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.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.
Affiliation: Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.Show MeSH
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Mentions: The STAT3 and NF-κB signaling pathways play an important role in tumor cell survival and growth. Therefore, we analyzed the effects of 2-MS on the growth and survival of a panel of human tumor cell lines. We first examined the 2-MS's effects on HeLa cells using a real-time cell analysis system. As shown in Figure. 7(a), 2-MS exhibited inhibitory effects on HeLa cells and 10 μM 2-MS totally inhibited the cell growth. 2-MS inhibited the growth of all human tumor cell lines we examined with an IC50 between 2.5 to 12.5 μM (Figure. 7b). Many STAT3 and NF-κB pathway inhibitors inhibit cell growth by inducing apoptosis.(9–14,24,25) Therefore, we tested the ability of 2-MS to induce apoptosis. As shown in Figure. 7(c), 2-MS mostly induced necrosis of the tumor cells, as indicated by the single PI staining. We also examined the effects of 2-MS on the PARP cleavage in the tumor cells. However, we did not detect the PARP cleavage caused by 2-MS (data not shown).
Affiliation: Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.