Abstract 5345: A novel small molecule, XZH-5 inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells

Abstract

Abstract Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite the fact the improved treatment for Rhabdomyosarcoma has resulted in a remarkable increase of overall survival, the children with metastatic Rhabdomyosarcoma still have only a 3-year failure-free survival rate of less than 30%. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in most types of cancer including human RMS. STAT3 is considered to be an oncogene due to its ability to promote malignancy in mice. Given the oncogenic functions of STAT3 and the promise of inhibiting it, directly targeting STAT3 signaling represents a potential therapeutic approach to treating Rhabdomyosarcoma. Using structure-based drug design, we developed a novel small molecule, named XZH-5. In this study, we characterized the inhibitory effects of XZH-5 on STAT3 phosphorylation in four Rhabdomyosarcoma cell lines. XZH-5 competes with/inhibits the STAT3-SH2 dimerization through phosphorylated Tyr705 in all four Rhabdomyosarcoma cell lines. We also demonstrated a similar inhibition of STAT3 phosphorylation and induction of apoptosis by a previously known small molecular STAT3 inhibitor Stattic in Rhabdomyosarcoma cells. These results supporting Rhabdomyosarcoma cell lines are sensitive to STAT3 inhibition. In addition, XZH-5 inhibited STAT3 DNA binding activity and the expression of STAT3 downstream genes including Bcl-2, Bcl-xl, Cyclin D1 and Survivin. The inhibition of STAT3 in Rhabdomyosarcoma cells resulted in the induction of apoptosis, reduction of colony forming ability, and inhibition of cell migration. Furthermore, XZH-5 inhibited IL-6-induced STAT3 phosphorylation and STAT3 nuclear translocation. In contrast, it had no effect on IFN-γ-induced STAT1 phosphorylation, indicating the more selective effects on STAT3. These results demonstrated that Rhabdomyosarcoma cells are sensitive to STAT3 inhibition and STAT3 is a therapeutic target. Our results also suggested that XZH-5 may serve as a potential therapeutic agent for targeting STAT3 for Rhabdomyosarcoma treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5345. doi:10.1158/1538-7445.AM2011-5345