Cellular mechanisms of resistance to platinum based chemotherapeutics are multifactorial and contribute to severe limitation in their use in clinical practice. They include molecular selleck chemical events inhibiting drug DNA interaction, such as a reduction in cisplatin accumulation inside cancer cells or inactivation by thiol containing species. Other mechanisms of resistance acting downstream to the initial reaction of cisplatin with DNA, include an increase in adduct repair and a decrease in induction of apoptosis. Pre clinical and clinical studies have demonstrated that HDAC inhibitors can enhance the anticancer activ ity of a variety of epigenetic as well as chemotherapeutic agents including cisplatin. For example, promising clinical trials combining platins as well as other che motherapeutics with HDAC inhibitors have been con ducted.

The ability of HDAC inhibitors to enhance the anti cancer activity of known chemothera peutic drugs is believed to be related to their function as positive regulators of gene transcription. As such, HDAC inhibitors have pleiotropic effects and can alter the expression of a wide variety of genes. In particular, HDAC inhibitor treatment has been shown to augment expression of genes such as cell cycle suppressor, p21, apoptotic factors related to both extrin sic and intrinsic pathways, and angiogenic factors such as HIF1a and VEGF. It is well established that HDAC inhibitors can enhance the anticancer activity of cisplatin in vitro in a variety of cancer cell models. Few studies exist, however, detailing the mechanism of enhanced anti cancer effects by HDAC inhibitors in combination with cisplatin.

For example, Rikiishi et al, correlated enhanced cytotoxicity by HDAC inhibitors in combination with cisplatin with reduced levels of the antioxidant intracellular reduced glutathione in an oral squamous cell carcinoma model. Our recent work has demonstrated that cisplatin treatment induces Activation of Transcription Factor 3, a member of the ATF/cyclic AMP response element binding family, regulates cisplatin induced cytotoxicity. ATF3 expression is induced by a wide variety of stress causing agents including hypoxia, metabolic stress and DNA damage. ATF3 is also induced in times of physiological stress such as liver regeneration, brain seizure, ischemia reperfu sion of the heart and kidney, and nerve damage.

ATF3 has been shown to play a role in apoptosis and proliferation, two cellular Drug_discovery processes critical for cancer progression. Divergence in function of ATF3 between a pro and anti apoptotic factor in cancer models is dependent on both cellular model and state of malig nancy. Activation of ATF3 by a wide array of stress signalling pathways have been demonstrated including DNA repair pathway components p53, the integrated stress response that is principally activated by hypoxia and metabolic stress, and the MAPKinase cascades.