YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma.
YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma.
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YC-1通过抑制肝细胞癌中的信号转导子和转录激活子3（STAT3）增强索拉非尼的抗肿瘤活性
DOI：
10.1186/1476-4598-13-7
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发表时间：
2014-01-13
期刊：
影响因子：
37.3
通讯作者：
Sun W
中科院分区：
文献类型：
--
作者：
Kong J;Kong F;Gao J;Zhang Q;Dong S;Gu F;Ke S;Pan B;Shen Q;Sun H;Zheng L;Sun W
背景传统的全身化疗不能提高肝细胞癌（HCC）患者的生存率。分子靶向治疗显示了肝癌治疗的前景，然而，靶向治疗的有效性的持续时间是有限的，联合治疗提供了改善疗效的潜力。方法索拉非尼，一种多激酶抑制剂，YC-1，一种可溶性鸟苷酸环化酶（sGC）激活剂，通过增殖测定，细胞周期分析和western印迹法在体外和原位和异位肝癌模型体内进行了测试。索拉非尼和YC-1的组合协同抑制HepG 2、BEL-7402和HCCLM 3细胞的增殖和集落形成。该组合还诱导S细胞周期停滞和凋亡，如通过活化的PARP和半胱天冬酶8所观察到的。索拉非尼和YC-1分别以剂量和时间依赖性方式抑制磷酸化STAT 3（p-STAT 3）（Y 705）的表达。在所有测试的HCC细胞系中，与单独使用索拉非尼或YC-1相比，索拉非尼和YC-1的组合显著抑制p-STAT 3（Y 705）（S727）、p-ERK 1/2、细胞周期蛋白D1和存活素的表达以及SHP-1活性。索拉非尼-YC-1组合可显着抑制HepG 2肿瘤异种移植物的生长，通过PCNA和PARP观察到细胞增殖减少和细胞凋亡增加。在HCCLM 3原位模型中也证实了类似的结果。CD 31阳性血管减少，VEGF表达减少，这表明索拉非尼和YC-1对血管生成的联合作用。联合用药可降低p-STAT 3、cyclin D1和survivin的表达。结论联合用药可有效抑制肝癌细胞的生长。
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 blotin vitroand orthotopic and ectopic HCC modelsin 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.
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影响因子：
9.7
作者：
Chun, YS;Yeo, EJ;Park, JW
通讯作者：
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158.5
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作者：
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25.7
作者：
Blivet-Van Eggelpoel, Marie-Jose;Chettouh, Hamza;Desbois-Mouthon, Christele
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