世界胃肠病学杂志(英文版)
世界胃腸病學雜誌(英文版)
세계위장병학잡지(영문판)
WORLD JOURNAL OF GASTROENTEROLOGY
2007年
35期
4761-4770
,共10页
Histone deacetylase inhibitor%Biliary tract cancer%Cholangiocarcinoma%NVP-LAQ824%NVP-LBH589
AIM: To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer.METHODS: Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21WAF-1/CIP-1,PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1.RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 (3 d) 0.11 and 0.05 μmol/L,respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1/CIP-1, induction of apoptosis (PARP cleavage), and cell cycle arrest at G2/M checkpoint. After 28 d, NVPLBH589 significantly reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation (MIB-1).CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.