Treatment of pancreatic cancer with two novel histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589

Abstract

4624 Background: Pancreatic cancer is the fifth to sixth leading cause of cancer death in Europe and up to 90% of patients will present with locally advanced or metastatic disease. Unfortunately, little progress has been obtained from chemotherapy regimens in the past decade. Treatment with histone deacetylase inhibitors, like NVP-LAQ824 and NVP-LBH589, either alone or in combination with conventional chemotherapy may be a novel alternative. Methods: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic 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, acH4, p42/p44, Phospho-p42/p44, AKT, Phospho- AKT, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1. Results: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines (mean IC50 (6d) 0.06 and 0.03 μM, respectively) and was associated with hyperacetylation of nucleosomal histones H4, increased expression of p21WAF-1, and cell cycle arrest at G2/M-checkpoint. After 21 d, NVP-LBH589 alone reduced tumor mass in vivo by 70% and in combination with gemcitabine by 81% in comparison to placebo for cell line L3.6 pl. Further analysis of the tumor specimens revealed slightly increased apoptosis (TUNEL) and no significant reduction of cell proliferation (MIB-1). Protein levels of p42/p44, and AKT remained stable, whereas levels of Phospho-p42/p44 and Phospho-AKT increased. Conclusions: Our findings suggest that NVP-LBH589 > NVP-LAQ824 are active against human pancreatic cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine, although the precise mechanism of drug action is not yet completely understood. Therefore, further preclinical and clinical evaluation of this new drug for the treatment of pancreatic cancer is recommended. No significant financial relationships to disclose.