321 POSTER Mechanism of action analysis in cell-based screens using Gleevec and Velcade as examples

Abstract

Cancer chemoprevention is the use of nontoxic natural or synthetic agents to decrease the risk of malignant tumor development. Increasing evidence implies that epigenetic silencing mechanisms play a major role in human carcinogenesis. A tightly regulated balance exists in normal cells between histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, and when this balance is disrupted, cancer development may ensue. Deacetylation of histones is mediated by some HDACs and ensures a condensed and, therefore, inactive chromatin conformation, while histone acetylation, catalyzed by HATs, allows histone disengagement from DNA, DNA association with transcription factors, and subsequent gene transcription. HDACs can be divided into four classes, based on their structure and sequence homology: class I consists of HDAC1, -2, -3, and -8; class II includes HDAC4, -5, -6, -7, -9, and -10; class IV consists of HDAC11; and an NAD-dependent class III type of HDAC, called sirtuins. Several natural products known for their cancer chemopreventive potential modulate the activity of HDACs. Recent studies showed that besides being a potent phase II enzyme inducer, sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, is also an inhibitor of HDACs. This fact provides a novel chemoprevention mechanism by which SFN might promote cell cycle arrest and apoptosis in vivo. Further, there is evidence that the deacetylation of p53 and Myc by sirtuins might be involved in the prevention of cancer. Resveratrol, another natural product produced by several plants, including peanuts, mulberries, and grapes, upregulates sirtuin 1. Finally, we discuss enzyme- and cell-based assays with the aim of screening plant extracts and isolated compounds for their activities on HDACs. These assays not only allow a deeper insight into the mode of action of HDAC modulators but also increase our knowledge of the beneficial effects of natural products.