Abstract 3844: A novel sorafenib-derivative SC-1 induces apoptosis in breast cancer cells through STAT3 inhibition

Abstract

Abstract Background: STAT3 has emerged as a novel potential anti-cancer target and its signaling is constitutively activated in various cancers including breast cancer. Our previous study has shown that STAT3 is a major kinase-independent target of sorafenib in HCC. (J Hepatol. 2011). We have designed and synthesized a series of sorafenib analogues devoid of sorafenib's kinase inhibition activity, some of which showed stronger p-STAT3 inhibition and apoptosis-inducing effects than sorafenib in HCC cells (Eur J Med Chem. 2011). Here, we tested the efficacy of our previously published sorafenib derivative, SC-1, in breast cancer cells and examined the drug mechanism. Methods: breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Tyrosine Phosphatase Assay Kit was used for SHP-1 activity assay. Gene silencing was done by small interference RNA (siRNA). In vivo efficacy of Sorafenib, and SC-1 were tested in xenografted nude mice. Results: Sorafenib, and SC-1 induced apoptosis in association with down-regulation of P-STAT3 and its downstream proteins Cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA MB-468, MDA MB-231, MDA MB-453, SKBR-3, MCF-7) and the apoptotic effects induced by SC-1 were more potent than Sorafenib. Over-expression of STAT3 in MDA MB-468 cells protected cells from apoptosis induced by sorafenib and SC-1. Moreover, SC-1 up-regulated higher SHP-1 activity than sorafenib by in vitro phosphatase assays. Knockdown of SHP-1, but not SHP-2 or PTP-1B, by siRNA reduced apoptosis induced by SC-1. Importantly, SC-1 showed in vivo efficacy in MDA-468 xenografted tumor. These data indicated that inhibiton of P-STAT3 by up-regulating SHP-1 activity mediated apoptotic effects of sorafenib and SC-1 in breast cancer cells. Conclusions: novel sorafenib-derivative SC-1 induces apoptosis in breast cancer cells through SHP-1 dependent p-STAT3 inhibition. (Supported by NSC100-2325-B-002-036, NSC98-2320-B-010-005-My3 and NSC-100-2325-B-010-007, VGHTPE V100D-005-4, 101DHA0100318, and 101DHA0100230.) Keyword: Sorafenib, breast cancer, STAT3, SHP-1, apoptosis Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3844. doi:1538-7445.AM2012-3844