RRC ID 43666
著者 Lachenmayer A, Toffanin S, Cabellos L, Alsinet C, Hoshida Y, Villanueva A, Minguez B, Tsai HW, Ward SC, Thung S, Friedman SL, Llovet JM.
タイトル Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib.
ジャーナル J Hepatol
Abstract BACKGROUND & AIMS: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.
METHODS: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 three liver cancer cell lines and a murine xenograft model.
RESULTS:Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and HDAC5 mRNAs was 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.
CONCLUSIONS: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.
巻・号 56(6)
ページ 1343-50
公開日 2012-6-1
DOI 10.1016/j.jhep.2012.01.009
PII S0168-8278(12)00100-6
PMID 22322234
PMC PMC3355195
MeSH Animals Antigens, CD Antineoplastic Combined Chemotherapy Protocols / therapeutic use* Apoptosis / drug effects Autophagy Benzenesulfonates / administration & dosage* Cadherins / genetics Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / pathology Drug Synergism Histone Deacetylase Inhibitors / administration & dosage* Humans Hydroxamic Acids / administration & dosage* Indoles Inhibitor of Apoptosis Proteins / genetics Liver Neoplasms / drug therapy* Liver Neoplasms / pathology Niacinamide / analogs & derivatives Panobinostat Phenylurea Compounds Polymorphism, Single Nucleotide Pyridines / administration & dosage* RNA, Messenger / analysis Sorafenib Survivin Xenograft Model Antitumor Assays
IF 20.582
引用数 121
WOS 分野 GASTROENTEROLOGY & HEPATOLOGY
リソース情報
ヒト・動物細胞