Pancreatic cancer is the fifth to sixth leading cause of cancer death in Europe and the fourth leading cause of cancer death in the USA. The lethality of this malignancy is demonstrated by the fact that the annual incidence is approximately equal to the annual deaths. Unfortunately, carcinoma of the pancreas is increasing in incidence, and its exact risk factors are poorly understood. Although surgical resection remains the only chance of cure, less than 10% of patients diagnosed with pancreatic cancer can actually have a curative (R0) resection, since up to 90% of patients will present with locally advanced or metastatic disease. In addition, there is a high rate of relapse, even in patients who receive adjuvant therapy. Therefore, novel therapeutical approaches are desperately needed.
A research article to be published on 21 June 2008, in the World Journal of Gastroenterology addresses this question. The research team led by Prof. Wiedmann from the Department of Internal Medicine II, University of Leipzig, Germany, investigated in vitro and in vivo treatment of pancreatic cancer cell lines with novel histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 manufactored by Novartis company.
Histones (positively charged proteins) are the major components of chromatin. Histone acetylation and deacetylation modulate chromosome structure and regulate gene transcription. Two families of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), activate and repress gene expression, respectively. Aberrant HAT or HDAC activity is associated with various epithelial and hematologic cancers. HDACs may play an important role in human oncogenesis through HDAC-mediated gene silencing and interaction of HDACs with proteins involved in tumorigenesis. HDAC inhibition could potentially restore normal processes in transformed cells without affecting normal cells.
As a result of the study, in vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histones H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and increased apoptosis. In the mouse model, NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.
These findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer, although the precise mechanism of in vivo drug action is not yet completely understood. Therefore, further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.