Will targeting ATM/ATR activity increase the anti-cancer efficacy of histone deacetylase inhibitors?

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Histone deacetylase inhibitors (HDIs) have been hailed as a new class of wonder drugs in the fight against cancer; they demonstrate anti-cancer specificity both in proliferating and non-proliferating cells (1), a much revered characteristic for any anti-cancer treatment. Currently, a number of these drugs are in Phase II clinical trials (2). We have recently demonstrated that HDIs possess checkpoint-dependent tumour selective cytotoxicity. HDI treatment normally activates a G₂ phase checkpoint that is defective in a wide spectrum of immortalizes, virally transformed and tumour cell lines. Drug sensitive (tumour) cells enter an aberrant mitosis which is lethal and they rapidly die from apoptosis (3). Normal cells and tissue with an intact checkpoint are resistant to the cytotoxic effect of these drugs. HDIs inhibit the activity of class I and II protein deacetlyases resulting in the rapid hyperacetylation of a range of cellular proteins, including chromatin histones (4). This leads to changes in the chromatin structure altering between 2-10% of gene transcription. One gene that is commonly up-regulated by HDI treatment is the cell cycle inhibitor p21^WAF1, and its increased expression contributes to anti-proliferative effects of drug treatment. We have shown that this p21up-regulation correlates with reduced cytotoxicity of HDIs by the inhibition of apoptosis (5). Preliminary data from our laboratory and others (6) indicate that ATM/ATR may be involved in the up-regulation of p21 in response to HDIs. The involvement of both ATM and ATR in this process will be determined. Although targeting ATM/ATR directly will prevent p21 up-regulation in response to HDI, ATM/ATR have also been implicated in the HDI sensitive G₂ checkpoint, therefore the elucidation of the pathway involved in the up-regulation of p21 will identify more suitable targets to use in combination therapy with HDIs. Preliminary data will be presented which indicates that ATR is involved in this HDI-induced p21 up-regulation, and a number of potential down stream regulators identified. 1. Burgess, A., Ruefli, A., Beamish, H., Warrener, R., Saunders, N., Johnstone, R. & Gabrielli, B. (2004). Oncogene, 23, 6693-701. 2. Kelly, W. et al. (2003). Clin Cancer Res. 9:3578-88. 3. Warrener, R., Beamish, H., Burgess, A., Waterhouse, N.J., Giles, N., Fairlie, D. & Gabrielli, B. (2003). Faseb J, 17, 1550-2. 4. Beamish, H. Warrener, R., Gabrielli, B. (2004) Methods in Molec. Biol. 281: 245-60. 5 Burgess, A.J., Pavey, S., Warrener, R., Hunter, L.J., Piva, T.J., Musgrove, E.A., Saunders, N., Parsons, P.G. & Gabrielli, B.G. (2001). Mol Pharmacol, 60, 828-37. 6 Ju, R. & Muller, M.T. (2003). Cancer Res, 63, 2891-7