Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib.
Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib.
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DOI：
10.1016/j.jhep.2012.01.009
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发表时间：
2012-06
影响因子：
25.7
通讯作者：
Llovet, Josep M.
中科院分区：
文献类型：
--
作者：
Lachenmayer, Anja;Toffanin, Sara;Cabellos, Laia;Alsinet, Clara;Hoshida, Yujin;Villanueva, Augusto;Minguez, Beatriz;Tsai, Hung-Wen;Ward, Stephen C.;Thung, Swan;Friedman, Scott L.;Llovet, Josep M.
肝细胞癌是一种异质性肿瘤，索拉非尼是唯一被批准的全身治疗方法。组蛋白脱乙酰酶(HDAC)在癌症中普遍表达异常，是治疗的重要靶点，但其在肝细胞癌发病机制中的作用尚不清楚。我们分析了11个HDAC在人肝癌细胞中的表达，并评估了PAN-HDAC抑制剂Panobinostat单独和联合索拉非尼在肝癌临床前模型中的疗效。分析了334例人肝癌的基因表达和拷贝数变化，同时评价了潘诺比妥和索拉非尼在3种肝癌细胞系和一种小鼠异种移植模型中的作用。分别在91例和243例肝细胞癌中发现和验证了HDAC的异常表达。HDAC3和5mRNAs的上调与DNA拷贝数的增加显著相关。用潘诺比坦抑制HDACs在体内和体外都有很强的抗肿瘤作用，而加入索拉非尼则增强了抗肿瘤作用。细胞存活率和增殖率下降，而细胞凋亡率和自噬增加。Panobinostat增加组蛋白H3和HSP90乙酰化，下调BIRC5(Survivin)，上调CDH1。帕诺比妥和索拉非尼联合治疗可显著降低肝癌移植瘤的血管密度，其中最显著的是缩小肿瘤体积和提高存活率。肝细胞癌中存在多种HDACs的异常表达和HDAC3、HDAC5的拷贝数增加。在肝细胞癌模型中，潘诺比妥和索拉非尼联合治疗显示了最高的临床前疗效，为这一新组合的临床研究提供了理论基础。
Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer. Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in 3 liver cancer cell lines and a murine xenograft model. Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and 5 mRNAs were significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased Histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts. Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination.
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影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
29.4
作者：
Llovet, Josep M.;Chen, Yingbei;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
13.3
作者：
Liu, Yuan-Ling;Yang, Pei-Ming;Chen, Ching-Chow
通讯作者：
Chen, Ching-Chow
影响因子：
3.3
作者：
Prince, H. Miles;Bishton, Mark J.;Johnstone, Ricky W.
通讯作者：
Johnstone, Ricky W.