Current Drug Targets - Volume 15, Issue 13, 2014

Oxidative stress is linked with many pathologies ranging from cancer to neurodegenerative disorders and antioxidants have presumably therapeutic value in such diseases. In this review, we categorize different direct and indirect mechanisms by which antioxidants exert their action. These include scavenging and metal chelating effects, mimicking the antioxidant enzymes or upregulation of their expression, activation of nuclear factor erythroid 2-related factor 2 (Nrf2), increasing the activity of sirtuins and inhibition of pro-oxidant enzymes among others. Recent findings on the most frequently investigated antioxidants including polyphenolics, thiolics, spin trapping agents, SOD mimetics, inducers of heme oxygenase-1 and nitric oxide synthase, activators of Nrf2, NADPH oxidase inhibitors and herbal supplements are summarized. Furthermore, the antioxidant effects of drugs that are clinically used for other pharmacological purposes including ACE inhibitors and statins are discussed. Cost-effectiveness and adverse effects of antioxidants are also evaluated. Since antioxidant therapy has failed in many instances, we have classified the reasons that may explain these shortcomings in different categories. Novel approaches to antioxidant therapy, that include mitochondria-targeting drugs, antioxidant gene therapy and approaches for improvement of cell uptake and alteration of subcellular compartment localization are also described. In the end, “shadows” that are shortcomings of antioxidant therapy as well as “lights” that include positive outcomes are addressed. It is concluded that if we learn from failures, invest on agents with higher potential and take advantage of novel emerging approaches, antioxidants could be an asset for the management of certain carefully chosen oxidative stress-related diseases.

Optimal identification of the risk of developing cardiotoxicity upon trastuzumab (TZM) treatment appears necessary as this risk may impair treatment compliance and compromise long-term recovery. To better understand and predict cardiac toxicity, the molecular mechanisms underlying this phenomenon need to be known. HER2 is present at the cell surface of cardiomyocytes. Neuregulin is produced by cardiac endothelial cells and binds to HER4, thus leading to dimerization with HER2 and subsequent cell signaling necessary for normal cardiac function. Decreasing HER2 activity has a major impact on cardiomyocyte function. However, the precise molecular mechanisms responsible for TZM-induced cardiac dysfunction are still unclear. This mini-review aims to summarize genetic, pharmacological and medical data helping to identify mechanisms that could explain cardiotoxicity. Of potential interest, these mechanisms highlight the importance of HER2 genetic polymorphism (Val655Ile) in the identification of patients at risk of developing TZMinduced cardiac effects.

Rituximab has demonstrated a major effect in B-cell lymphoma and in a wide range of autoimmune disorders. Unfortunately, the blood-brain-barrier excludes the disorders restricted to the central nervous system (CNS) from the action of rituximab. The progressive phase of multiple sclerosis (MS) is a prototypical CNS autoimmune disorder characterized by an intrathecal compartmentalization of inflammation resisting all the available immunosuppressive treatments. As a consequence, intrathecal therapeutics are promising new approach in progressive MS. We first review data gathered from animal models and human off-label intrathecal rituximab use in CNS lymphomas, then summarize the recent evidence supporting the need for trials based on the intrathecal use of rituximab in multiple sclerosis. The experience obtained in these settings offers valuable preliminary data for future studies in CNS autoimmunity.

Androgen and androgen receptor (AR) play a critical role in the development of prostate cancer. Androgen deprivation therapy (ADT) has become the therapeutic mainstay for patients with metastatic prostate cancer. ADT can reduce the serum testosterone level from the normal range between 500 and 600 ng/dl to the castrate level. Following surgical castration, the serum testosterone level decreases to less than 20 ng/dL (0.69 nmol/L) in about three quarters of the patients. Although insufficient suppressions of the serum testosterone level following ADT have not been well recognized to date, the failure in achieving the castrate level of testosterone may have an adverse impact on survival in men with prostate cancer. Although circulating testosterone levels following castration do not necessarily reflect the amount of intraprostatic testosterone or dihydrotestosterone, testosterone during ADT mainly derives from intratumorally synthesized precursors and adrenal androgens. The advent of new agents represented by abiraterone acetate and enzalutamide, which target adrenal or intraprostatic androgen biosynthesis and AR signaling, respectively, has retrieved interest in testosterone levels during ADT. We critically reviewed androgen metabolism and its significance in prostate cancer biology and treatment to promote their better understanding and management of men with prostate cancer.

Although the extended RAS analysis allows a better identification of patients potentially candidates to anti- EGFR monoclonal antibodies, a significant proportion of tumours may still reveals refractory to such a treatment approach. In these latter cases patients are then exposed to unnecessary toxicities without clinical benefit. Among many further biological factors that may have a role in determining resistance/sensitivity to EGFR-inhibitors, the EGFR itself, other members of the HER family (i.e. HER-2 and HER-3) as well as other surface receptors such as the IGF-1 receptor seem of particular interest. Preclinical models have shown that these receptors are biologically connected to each other and able to directly or indirectly influence the downstream molecular pathways. In the presence of abnormal expression of these biological determinants, intracellular pathways may become independent from the receptor-targeting treatment thus making therapies directed against the receptor ineffective. Clinical observations and translational studies seem to confirm these findings. The Authors have reviewed the literature and have selected recent clinical reports focusing on translational research on the EGFR itself or on other molecules that may interfere with this pathway. We also discuss potential future developments in this area.

Growing evidence indicates that overproduction of reactive oxygen species (ROS) plays a prominent role in the development of cardio- and cerebro-vascular diseases. Among the mechanisms identified to produce oxidative stress in the vascular wall, those mediated by membrane-bound NAD(P)H oxidases represent a major one. NAD(P)H oxidases are a family of enzymes that generate ROS both in phagocytic and non-phagocytic cell types. Vascular NAD(P)H oxidase contains the membrane-bound subunits Nox1, Nox2 (gp91phox), Nox4 and p22phox, the catalytic site of the oxidase, and the cytosolic components p47phox and p67phox. Rac1 (Ras-related C3 botulinum toxin substrate1) is a small GTPase essential for the assembly and activation of NADPH oxidase. Several molecular and cellular studies have reported the involvement of Rac1 in different cardiovascular pathologies, such as vascular smooth muscle proliferation, cardiomyocyte hypertrophy, endothelial cell shape change, atherosclerosis and endothelial dysfunction in hypertension. In addition, increased activation of NADPH oxidase by Rac1 has been reported in animals and humans after myocardial infarction and heart failure. The Rac1/NADPH pathway has also been found involved in different pathologies of the cerebral district, such as ischemic stroke, cognitive impairment, subaracnoid hemorrhage and neuronal oxidative damage typical of several neurodegenerative disorders. In addition, thrombotic events are an important step in the onset of cardio- and cerebrovascular diseases. Rac1 has been found involved also in platelet activation, inducing actin polymerization and lamellipodia formation, which are necessary steps for platelet aggregation. Taken together, the evidence candidates Rac1 as a new pharmacological target of cardiovascular and cerebrovascular diseases. Although the involvement of Rac1 in the beneficial pleiotropic effects of drugs such as statins is well known, and the onset of numerous side effects has raised concern for the management of some patient groups. Interestingly, a novel selective Rac1 inhibitor, NSC23766, has recently been introduced; its use has been reported mainly in the oncology field. Future studies are needed to extend its application to cardio- and cerebro-vascular diseases, and translate its use to humans.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world and has not seen improved survival rates over the past few decades. Current treatment plans include surgery, radiation therapy, and chemotherapy, but these are relatively ineffective options for recurrent or metastatic tumors. Therefore, there is a high priority for new therapies that specifically target the resistant HNSCC cancer stem cells (CSCs), a subpopulation responsible for tumor initiation and metastasis. Given their vast effects on gene expression and biological processes, including stem cell capabilities, non-coding RNAs (ncRNAs) have become a promising new repertoire of genes to investigate as potential diagnostic or therapeutic targets. This review presents a comprehensive overview of current investigative studies that can contribute to our understanding of the still tentative link between ncRNA and the biology of HNSCC cancer stem cells. In doing so, we aim to analyze the potential role of stem cell-related ncRNAs in the development of molecularly targeted cancer therapy for HNSCC. Although the majority of updated knowledge on HNSCC and ncRNA focuses heavily on microRNA, we chose to give considerable attention to the promise of other classes of ncRNAs (lncRNA, piRNA, and snoRNA), many of which are not yet well characterized or are yet to be discovered, and thus represent a potentially exciting and untapped pool of molecular targets or biomarkers in HNSCC therapy.