A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer.
A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer.
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DOI：
10.3390/ph9020018
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发表时间：
2016-03-24
期刊：
影响因子：
--
通讯作者：
Kimchi ET
中科院分区：
文献类型：
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作者：
Tagaram HR;Desai D;Li G;Liu D;Rountree CB;Gowda K;Berg A;Amin S;Staveley-O'Carroll KF;Kimchi ET
肝细胞癌（HCC）是世界上第三大致命癌症。由于标准治疗方法有限，迫切需要新的治疗策略。Erk、Akt和stat3通路的激活与HCC的预后有关。Se,Se ' -1,4-phenylenebis（1,2-乙二基）bisisoselenourea （PBISe）是一种含硒的MAPK和PI3激酶抑制剂，在多种实验模型中有效抑制肿瘤发生。我们研究的目的是证明pise在HCC治疗中的潜在作用。在体外对四种人肝癌细胞系和小鼠自发性肝癌模型中研究了PBISe的抗增殖和促凋亡能力。通过细胞活力测定和caspase 3/7、PARP切割、annexin-V和TUNEL测定细胞凋亡来抑制肿瘤生长。pise在PI3激酶、MAPK和STAT3信号传导中的作用通过Western blotting检测。在小鼠自发性肝癌中，使用MRI监测pise对肿瘤大小的体内影响。分析pbise处理小鼠肝组织的血管生成、增殖和信号通路标志物。总体而言，PBISe激活了caspase-3/7，增加了DNA片段化，这与PARP切割增加正相关。pise通过抑制PI3K、MAPK和STAT3信号通路促进细胞凋亡，显著降低肿瘤大小（p < 0.007）。pbise治疗的肿瘤降低了生存标记物PCNA和血管生成标记物Vegf-A、Vegf-R3和CD34。这些结果证明了PBISe通过抑制肿瘤生长和促进肿瘤凋亡来治疗HCC的化疗作用。
Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. New treatment strategies are desperately needed due to limited standard therapies. Activation of the Erk, Akt, and STAT3pathways is implicated in the prognosis of HCC. The Se,Se′-1,4-phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), is a selenium-containing MAPK and PI3 kinase inhibitor, effectively inhibit tumorigenesis in a variety of experimental models. The aim of our study is to demonstrate the potential role of PBISe in the treatment of HCC. The anti-proliferative and pro-apoptotic ability of PBISe is studied in vitro in four human HCC cell lines and in vivo in a spontaneous murine HCC model. Inhibition of cancer growth was performed by cell viability assay and apoptosis by caspase 3/7, PARP cleavage, annexin-V, and TUNEL assays. Role of PBISe on PI3 kinase, MAPK and STAT3 signaling is determined by Western blotting. In vivo effects of PBISe on tumor sizes were monitored using MRI in a spontaneous murine HCC. Liver tissues from the PBISe-treated mice are analyzed for angiogenesis, proliferation, and signaling pathway markers. Overall, PBISe activated caspase-3/7 and increased DNA fragmentation, which is positively correlated with the increased PARP cleavage. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling with significant reduction in the tumor sizes (p < 0.007). PBISe-treated tumors reduced survival marker PCNA, and angiogenesis markers Vegf-A, Vegf-R3 and CD34. These results demonstrate the chemotherapeutic effects of PBISe, by inhibiting tumor growth and facilitating tumor apoptosis for HCC treatment.