oa Editorial [Hot Topic: Development of Drugs Interfering with Apoptosis (Executive Guest Editor: Sebastiano Cavallaro)]

Apoptosis is implicated in numerous pathological processes that include cancer, autoimmune disorders and neurodegenerative diseases. Recent advances in the knowledge of the molecular mechanisms underlying apoptosis is providing a number of potential therapeutic targets and allowing the development of effective drugs that are able to interfere with this type of programmed cell death. This issue of Current Pharmaceutical Design provides an extensive overview of the latest findings concerning the molecular mechanisms of apoptosis and drugs that are able to interfere with these mechanisms. This issue, in particular, comprises the following 9 contributions: Pezzino et al. discuss how the identification, prioritization and validation of preclinical therapeutics can be achieved through genomic analysis of critical pathways and networks in neuronal apoptosis and survival. They highlight the importance of the system biology approach in the process of drug discovery. They discuss how apoptosis and survival, depend on the activity of an integrated network of genes and their encoded proteins [1]. Seaborn et al. discuss the anti-apoptotic effects of Pituitary adenylate cylase-activating polypeptide (PACAP) and its derivative, together with their potential use in the treatment of post-traumatic lesions, neurodegenerative diseases, cardiac ischemia, and retinopathy [2]. Cavallucci and D'Amelio review evidence linking apoptosis to brain diseases and discuss how knowledge of these mechanisms are leading to novel therapeutics. They focus on neurodegeneration, the pathogenetic role of apoptosis in brain diseases, and on recent progress of apoptosis-based therapies [3]. Sureda et al. discuss potential pathways involved in the pathogenesis of neurodegenerative diseases, highlighting current pharmacological drug targets in neuronal apoptosis prevention and examine drugs that may have a neuroprotective effect [4]. Silva et al. discuss the use of a yeast model system to reveal novel drug targets against apoptosis. The use of this cell model is contributing to understand the function of Bcl-2 family of proteins and identify novel therapeutic opportunities [5]. Wasierska-Gadek and Maurer review the impact of inhibiting individual cellular CDKs on apoptosis. They discuss in detail the molecular mechanisms by which CDK inhibitors are able to bypass chemoresistance in tumor cells and trigger apoptosis. Pharmacological utility of CDK inhibitors is considered not only in the treatment against cancer, but also in neurodegenerative and cardiovascular diseases [6]. Grimm et al. review recent development of drugs, which interfere with apoptosis and are currently used or tested for treatment of breast cancer. These novel agents include those targeting the extrinsic pathway such as Fas, tumor necrosis factor-alpha and tumor necrosis factor related apoptosis-inducing ligand, as well as drugs targeting the intrinsic Bcl-2 family pathway, or drugs inhibiting repair enzymes such as Poly (ADP-ribose) polymerase (PARP) inhibitors [7]. Johnson et al. consider the possibility that the endoplasmic reticulum stress response (ERSR) could be a possible target to develop chemotherapeutic agents to induce toxicity in glioma cells, and describe how the ERSR pathway mediates apoptosis and how it can be a target for small molecules to cause cell death [8]. Li et al. discuss the molecular mediators of cellular apoptosis, the respective mechanisms by which these mediators are dysregulated in cellular oncogenesis, the history and development of both nucleic-acid and amino-acid based drugs, and techniques to achieve intracellular delivery of these biologics. Finally, recent applications where pro-apoptotic functionality has been achieved through delivery of intracellularacting biomacromolecular drugs are described [9].