YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 STAT3 in hepatocellular carcinomaReport as inadecuate




YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 STAT3 in hepatocellular carcinoma - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 13:7

First Online: 13 January 2014Received: 03 August 2013Accepted: 06 January 2014DOI: 10.1186-1476-4598-13-7

Cite this article as: Kong, J., Kong, F., Gao, J. et al. Mol Cancer 2014 13: 7. doi:10.1186-1476-4598-13-7

Abstract

BackgroundTraditional systemic chemotherapy does not provide survival benefits in patients with hepatocellular carcinoma HCC. Molecular targeted therapy shows promise for HCC treatment, however, the duration of effectiveness for targeted therapies is finite and combination therapies offer the potential for improved effectiveness.

MethodsSorafenib, a multikinase inhibitor, and YC-1, a soluble guanylyl cyclase sGC activator, were tested in HCC by proliferation assay, cell cycle analysis and western blot in vitro and orthotopic and ectopic HCC models in vivo.

ResultsIn vitro, combination of sorafenib and YC-1 synergistically inhibited proliferation and colony formation of HepG2, BEL-7402 and HCCLM3 cells. The combination also induced S cell cycle arrest and apoptosis, as observed by activated PARP and caspase 8. Sorafenib and YC-1 respectively suppressed the expression of phosphorylated STAT3 p-STAT3 Y705 in a dose- and time-dependent manner. Combination of sorafenib and YC-1 significantly inhibited the expression of p-STAT3 Y705 S727, p-ERK1-2, cyclin D1 and survivin and SHP-1 activity compared with sorafenib or YC-1 used alone in all tested HCC cell lines. In vivo, sorafenib-YC-1 combination significantly suppressed the growth of HepG2 tumor xenografts with decreased cell proliferation and increased apoptosis observed by PCNA and PARP. Similar results were also confirmed in a HCCLM3 orthotopic model. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, which suggested a combinational effect of sorafenib and YC-1 on angiogenesis. The reduced expression of p-STAT3, cyclin D1 and survivin was also observed with the combination of sorafenib and YC-1.

ConclusionsOur data show that sorafenib-YC-1 combination is a novel potent therapeutic agent that can target the STAT3 signaling pathway to inhibit HCC tumor growth.

KeywordsYC-1 Sorafenib Hepatocellular carcinoma STAT3 Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-7 contains supplementary material, which is available to authorized users.

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