4149 Background: Chromatin remodelling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. NVP-LAQ824 and NVP-LBH589 are two novel chemical entities belonging to a cinnamic hydroxamic acid class of compounds. Little is known about their efficacy for the treatment of 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 p21WAF-1, acH3Lys9 and acH4, cell cycle analysis, PARP assay, 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 (3d) 0.08 and 0.04 μM, respectively) and was associated with hyperacetylation of nucleosomal histones H3 and H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and induction of apoptosis (PARP cleavage). After 28 d, NVP-LBH589 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 (TUNEL) and reduced cell proliferation (MIB-1). Conclusions: Our findings suggest that NVP-LBH589 > 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. No significant financial relationships to disclose.
Clinical Significance of Cell Cycle–and Apoptosis-Related Markers in Biliary Tract Cancer