Current Drug Targets (v.15, #13)

Pharmacological Applications of Antioxidants: Lights and Shadows by Luciano Saso, Omidreza Firuzi (1177-1199).
Oxidative stress is linked with many pathologies ranging from cancer to neurodegenerative disorders and antioxidantshave presumably therapeutic value in such diseases. In this review, we categorize different direct and indirectmechanisms by which antioxidants exert their action. These include scavenging and metal chelating effects, mimickingthe 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 themost frequently investigated antioxidants including polyphenolics, thiolics, spin trapping agents, SOD mimetics, inducersof heme oxygenase-1 and nitric oxide synthase, activators of Nrf2, NADPH oxidase inhibitors and herbal supplements aresummarized. Furthermore, the antioxidant effects of drugs that are clinically used for other pharmacological purposes includingACE 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 shortcomingsin different categories. Novel approaches to antioxidant therapy, that include mitochondria-targeting drugs, antioxidantgene therapy and approaches for improvement of cell uptake and alteration of subcellular compartment localizationare also described. In the end, “shadows” that are shortcomings of antioxidant therapy as well as “lights” that includepositive outcomes are addressed. It is concluded that if we learn from failures, invest on agents with higher potential andtake advantage of novel emerging approaches, antioxidants could be an asset for the management of certain carefully chosenoxidative stress-related diseases.

Trastuzumab-Induced Cardiotoxicity: Is it a Personalized Risk? by Gerard A. Milano, Emilie Serres, Jean-Marc Ferrero, Joseph Ciccolini (1200-1204).
Optimal identification of the risk of developing cardiotoxicity upon trastuzumab (TZM) treatment appears necessaryas this risk may impair treatment compliance and compromise long-term recovery. To better understand and predictcardiac toxicity, the molecular mechanisms underlying this phenomenon need to be known. HER2 is present at the cellsurface of cardiomyocytes. Neuregulin is produced by cardiac endothelial cells and binds to HER4, thus leading to dimerizationwith HER2 and subsequent cell signaling necessary for normal cardiac function. Decreasing HER2 activity hasa major impact on cardiomyocyte function. However, the precise molecular mechanisms responsible for TZM-inducedcardiac dysfunction are still unclear. This mini-review aims to summarize genetic, pharmacological and medical datahelping to identify mechanisms that could explain cardiotoxicity. Of potential interest, these mechanisms highlight theimportance of HER2 genetic polymorphism (Val655Ile) in the identification of patients at risk of developing TZMinducedcardiac effects.

Intrathecal Rituximab Therapy in Multiple Sclerosis: Review of Evidence Supporting the Need for Future Trials by Mickael Bonnan, Sylvie Ferrari, Eric Bertandeau, Stephanie Demasles, Elsa Krim, Marie Miquel, Bruno Barroso (1205-1214).
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 actionof rituximab. The progressive phase of multiple sclerosis (MS) is a prototypical CNS autoimmune disorder characterizedby an intrathecal compartmentalization of inflammation resisting all the available immunosuppressive treatments. Asa consequence, intrathecal therapeutics are promising new approach in progressive MS. We first review data gatheredfrom animal models and human off-label intrathecal rituximab use in CNS lymphomas, then summarize the recent evidencesupporting the need for trials based on the intrathecal use of rituximab in multiple sclerosis. The experience obtainedin 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 deprivationtherapy (ADT) has become the therapeutic mainstay for patients with metastatic prostate cancer. ADT can reducethe serum testosterone level from the normal range between 500 and 600 ng/dl to the castrate level. Following surgicalcastration, the serum testosterone level decreases to less than 20 ng/dL (0.69 nmol/L) in about three quarters of thepatients. Although insufficient suppressions of the serum testosterone level following ADT have not been well recognizedto date, the failure in achieving the castrate level of testosterone may have an adverse impact on survival in men withprostate cancer. Although circulating testosterone levels following castration do not necessarily reflect the amount ofintraprostatic testosterone or dihydrotestosterone, testosterone during ADT mainly derives from intratumorallysynthesized precursors and adrenal androgens. The advent of new agents represented by abiraterone acetate andenzalutamide, which target adrenal or intraprostatic androgen biosynthesis and AR signaling, respectively, has retrievedinterest in testosterone levels during ADT. We critically reviewed androgen metabolism and its significance in prostatecancer biology and treatment to promote their better understanding and management of men with prostate cancer.

Beyond RAS: The Role of Epidermal Growth Factor Receptor (EGFR) and its Network in the Prediction of Clinical Outcome During Anti-EGFR Treatment in Colorectal Cancer Patients by Riccardo Giampieri, Giuseppe Aprile, Michela Del Prete, Luca Faloppi, Maristella Bianconi, Marta Bonotto, Giampiero Fasola, Stefano Cascinu, Mario Scartozzi (1225-1230).
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 furtherbiological 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 receptorseem of particular interest. Preclinical models have shown that these receptors are biologically connected to each otherand able to directly or indirectly influence the downstream molecular pathways. In the presence of abnormal expression ofthese biological determinants, intracellular pathways may become independent from the receptor-targeting treatment thusmaking therapies directed against the receptor ineffective. Clinical observations and translational studies seem to confirmthese findings. The Authors have reviewed the literature and have selected recent clinical reports focusing on translationalresearch on the EGFR itself or on other molecules that may interfere with this pathway. We also discuss potential futuredevelopments in this area.

Rac-1 as a New Therapeutic Target in Cerebro- and Cardio-Vascular Diseases by Albino Carrizzo, Maurizio Forte, Maria Lembo, Luigi Formisano, Annibale A. Puca, Carmine Vecchione (1231-1246).
Growing evidence indicates that overproduction of reactive oxygen species (ROS) plays a prominent role in thedevelopment of cardio- and cerebro-vascular diseases. Among the mechanisms identified to produce oxidative stress inthe vascular wall, those mediated by membrane-bound NAD(P)H oxidases represent a major one. NAD(P)H oxidases area family of enzymes that generate ROS both in phagocytic and non-phagocytic cell types. Vascular NAD(P)H oxidasecontains the membrane-bound subunits Nox1, Nox2 (gp91phox), Nox4 and p22phox, the catalytic site of the oxidase, andthe cytosolic components p47phox and p67phox. Rac1 (Ras-related C3 botulinum toxin substrate1) is a small GTPase essentialfor the assembly and activation of NADPH oxidase. Several molecular and cellular studies have reported the involvementof Rac1 in different cardiovascular pathologies, such as vascular smooth muscle proliferation, cardiomyocytehypertrophy, endothelial cell shape change, atherosclerosis and endothelial dysfunction in hypertension. In addition, increasedactivation of NADPH oxidase by Rac1 has been reported in animals and humans after myocardial infarction andheart 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 severalneurodegenerative disorders. In addition, thrombotic events are an important step in the onset of cardio- and cerebrovasculardiseases. Rac1 has been found involved also in platelet activation, inducing actin polymerization and lamellipodiaformation, which are necessary steps for platelet aggregation. Taken together, the evidence candidates Rac1 as a newpharmacological target of cardiovascular and cerebrovascular diseases. Although the involvement of Rac1 in the beneficialpleiotropic effects of drugs such as statins is well known, and the onset of numerous side effects has raised concernfor the management of some patient groups. Interestingly, a novel selective Rac1 inhibitor, NSC23766, has recently beenintroduced; its use has been reported mainly in the oncology field. Future studies are needed to extend its application tocardio- 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 notseen improved survival rates over the past few decades. Current treatment plans include surgery, radiation therapy, andchemotherapy, but these are relatively ineffective options for recurrent or metastatic tumors. Therefore, there is a high priorityfor new therapies that specifically target the resistant HNSCC cancer stem cells (CSCs), a subpopulation responsiblefor tumor initiation and metastasis. Given their vast effects on gene expression and biological processes, including stemcell capabilities, non-coding RNAs (ncRNAs) have become a promising new repertoire of genes to investigate as potentialdiagnostic or therapeutic targets. This review presents a comprehensive overview of current investigative studies that cancontribute to our understanding of the still tentative link between ncRNA and the biology of HNSCC cancer stem cells. Indoing so, we aim to analyze the potential role of stem cell-related ncRNAs in the development of molecularly targetedcancer 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, andsnoRNA), many of which are not yet well characterized or are yet to be discovered, and thus represent a potentially excitingand untapped pool of molecular targets or biomarkers in HNSCC therapy.