Inhibition of histone deacetylase for the treatment of biliary tract cancer: a new effective pharmacological approach.
OBJECTIVE
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 anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21( WAF-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 IC(50) (3 d) 0.11 and 0.05 micromol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21( WAF-1/CIP-1), induction of apoptosis (PARP cleavage), and cell cycle arrest at G2/M checkpoint. After 28 d, NVP-LBH589 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).


CONCLUSIONS
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.
Bluethner
Thilo
T
Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany.
Niederhagen
Manuel
M
Caca
Karel
K
Serr
Frederik
F
Witzigmann
Helmut
H
Moebius
Christian
C
Mossner
Joachim
J
Wiedmann
Marcus
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001661:Biliary Tract Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles; D051379:Mice; D008819:Mice, Nude; D000077767:Panobinostat; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C477361:LAQ824; D003841:Deoxycytidine; D000077767:Panobinostat; D000093542:Gemcitabine