Coupled with their ability to induce cell cycle arrest, apoptosis, and disruption of angiogenesis, HDAC inhibitors have been evaluated as cancer therapeutic agents. check this Currently the HDAC inhibitor, vorinostat, has been FDA approved for clinical use for treatment against cutaneous T cell lymphoma. cis Diamminedichloroplatinum is among the most active anti tumour agent used in human che motherapy and widely used in various tumour types including lung and ovarian cancers. Acquired resis tance and toxicities associated with treatment are major impediments inhibiting their efficacy. Cisplatin is pri marily considered as a DNA damaging agent that forms various types of bi functional adducts in reaction with cellular DNA.

Cisplatin becomes activated intra cellu larly by the aquation of one of two chloride leaving groups, and subsequently covalently binding to DNA, forming DNA adducts. The final cellular outcome of DNA adduct formation is generally apoptotic cell death, thought to occur through halting of cellular processes such as replication and transcription leading to pro longed G2 phase cell cycle arrest, and deregulation of signal transduction pathways involved in growth, differ entiation, and stress responses. Cellular mechanisms of resistance to platinum based chemotherapeutics are multifactorial and contribute to severe limitation in their use in clinical practice. They include molecular 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 Dacomitinib 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.