Abstract 3250: Sorafenib analogues SC-1 and SC-43 show better apoptotic effects than sorafenib through SHP-1 dependent STAT3 inhibition in breast cancer cells .

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). In addition, a protein tyrosine phosphatase SHP-1 has been demonstrated to downregulate p-STAT3 via its phosphatase activity. Here, we tested the efficacy of two sorafenib analogues, SC-1 and SC-43, 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 and SC-43 were tested in xenografted nude mice. Results: SC-1 and SC-43 induced more potent apoptosis than sorafenib, in association with downregulation 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). Overexpression of STAT3 in MDA MB-468 cells protected cells from apoptosis induced by sorafenib, SC-1, and SC-43. Moreover, SC-1 and SC-43 upregulated SHP-1 activity to a greater extent than sorafenib as measured by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed more efficacious antitumor activity and p-STAT3 downregulation than sorafenib in MDA-468 xenograft tumors. These data indicated that inhibiton of p-STAT3 by up-regulating SHP-1 activity mediated apoptotic effects of SC-1 and SC-43 in breast cancer cells. Moreover, a representative breast tumor tissue demonstrated reciprocal expression of SHP-1 and p-STAT3 in cancer cells and adjacent non-cancer breast tissue. Conclusions: Novel sorafenib analogues SC-1 and SC-43 induce apoptosis through SHP-1 dependent STAT3 inactivation and demonstrate greater potency than sorafenib in human breast cancer cells. (Supported by Yen Tjing Ling Medical Foundation; NSC 101-2325-B-075-006 and NSC 100-2325-B-010-007; VN101-03 (TVGH-NTUH Joint Research Program), V99-B1-016, and V100-D-005-4) Citation Format: Chun-Yu Liu, Ling-Ming Tseng, Kung-Chi Chang, Pei-Yi Chu, Jung-Chen Su, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen. Sorafenib analogues SC-1 and SC-43 show better apoptotic effects than sorafenib through SHP-1 dependent STAT3 inhibition in breast cancer cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3250. doi:10.1158/1538-7445.AM2013-3250