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Cancer Sci. 2011 Jul;102(7):1381-7. doi: 10.1111/j.1349-7006.2011.01932.x. Epub 2011 May 5.

Novel small molecule, XZH-5, inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells.

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Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.


Signal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in many types of human cancers and cancer cell lines and represents a promising target for cancer therapy. We previously reported that the STAT3 signaling pathway is constitutively activated in human rhabodomyosarcoma cell lines (RH28, RH30 and RD2). We also demonstrated that inhibition of the STAT3 pathway led to apoptosis in human rhabdomyosarcoma cells. In the present study, we investigated the inhibitory effects of a novel small molecule, XZH-5, on the STAT3 signaling pathway in human rhabdomyosarcoma cells. XZH-5 was designed based on STAT3 structure, and our idea was to design peptide mimics to bind to the phosphorylated Tyr705 site and the side pocket. We found that XZH-5 downregulated STAT3 phosphorylation. The inhibition of STAT3 by XZH-5 was confirmed by the inhibition of STAT3 DNA binding ability and the downregulation of STAT3 downstream genes, such as Bcl-2, Bcl-xL, Cyclin D1 and Survivin; we also demonstrated that blockade of STAT3 phosphorylation in human rhabdomyosarcoma cells with XZH-5 caused apoptosis and suppressed colony-forming ability and cell migration. In addition to reducing constitutive STAT3 phosphorylation, XZH-5 also exhibited the potency to block interleukin-6 (IL-6)-induced STAT3 phosphorylation and nuclear translocation but did not inhibit the stimulation of STAT1 phosphorylation by interferon (IFN)-γ. Our findings indicate that XZH-5 has the potential for targeting human rhabdomyosarcoma cells expressing constitutive STAT3.

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