2 novel histone deacetylase inhibitors against human pancreatic cancer: NVP-LBH589 and NVP-LAQ824

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.

Reference: Haefner M, Bluethner T, Niederhagen M, Moebius C, Wittekind C, Mossner J, Caca K, Wiedmann M. Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors World J Gastroenterol 2008; 14(23): 3681-3692
http://www.wjgnet.com/1007-9327/14/3681.asp.

Correspondence to: Marcus Wiedmann, Dr, Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, Leipzig 04103, Germany. wiedm@medizin.uni-leipzig.de
Telephone: +49-341-9712230 Fax: +49-341-9712239

World Journal of Gastroenterology (WJG), a leading international journal in gastroenterology and hepatology, has established a reputation for publishing first class research on esophageal cancer, gastric cancer, liver cancer, viral hepatitis, colorectal cancer, and H pylori infection and provides a forum for both clinicians and scientists. WJG has been indexed and abstracted in Current Contents/Clinical Medicine, Science Citation Index Expanded (also known as SciSearch) and Journal Citation Reports/Science Edition, Index Medicus, MEDLINE and PubMed, Chemical Abstracts, EMBASE/Excerpta Medica, Abstracts Journals, Nature Clinical Practice Gastroenterology and Hepatology, CAB Abstracts and Global Health. ISI JCR 2003-2000 IF: 3.318, 2.532, 1.445 and 0.993. WJG is a weekly journal published by WJG Press. The publication dates are the 7th, 14th, 21st, and 28th day of every month. WJG is supported by The National Natural Science Foundation of China, No. 30224801 and No. 30424812, and was founded with the name of China National Journal of New Gastroenterology on October 1, 1995, and renamed WJG on January 25, 1998.

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