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- W2039335903 abstract "Recently, we have reported that sorafenib sensitized hepatocellular carcinoma (HCC) cells to TRAIL via SHP-1 dependent inhibition of signaling transducer and activator of transcription 3 (STAT3) (Clinical Cancer Res, 2010). In addition, we identified the effect of sorafenib on STAT3 was independent to kinases and discovered a series of sorafenib derivatives as SHP-1 enhancers (J Hepatol, 2011; Euro J Med Chem, 2011). Here, we report effects of novel sorafenib derivatives (SC-40, SC-43 and SC-60) in HCC. SC-43 induced apoptotic cell death significantly and inhibited the phosphorylation of STAT3 (p-STAT3) at the concentration of 0.5 μM, which was more potent than sorafenib (5 μM). In addition, SC-60 also exhibited similar effects on down-regulating STAT3 transcription activity and subsequently inhibited the expression of STAT3-related proteins, including cyclin D1, survivin, and Mcl-1 in HCC cells. Furthermore, these analogues showed strong induction of SHP-1 activity while incubated with pure recombinant SHP-1 protein or SHP-1-containing cell extract at the concentrations of low nanomolar ranges. In addition, we found that SHP-2, sharing high homology in critical domains with SHP-1, was not affected neither in cultured HCC cells nor recombinant SHP-2 protein. Knockdown of SHP-1, but not SHP-2, by small interference RNA reduced apoptosis and reversed blockage of p-STAT3 induced by SC-43, 40, 60. Finally, three novel compounds, including SC-43, SC-40, and SC-60 all showed significant and better effects than sorafenib on growth inhibition of orthotopic and subcutaneous xenograft HCC tumors. In conclusion, targeting SHP-1 may be feasible for the treatment of HCC. 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 1915. doi:1538-7445.AM2012-1915" @default.
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- W2039335903 date "2012-04-15" @default.
- W2039335903 modified "2023-09-27" @default.
- W2039335903 title "Abstract 1915: Novel sorafenib derivatives (SC-40, SC-43 and SC-60) show better anti-tumor effects than sorafenib in hepatocellular carcinoma through SHP-1/STAT3-mediated signaling pathway" @default.
- W2039335903 doi "https://doi.org/10.1158/1538-7445.am2012-1915" @default.
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