Showing papers in "Current Drug Targets in 2014"

Therapeutic targeting of cancers with loss of PTEN function.

Abstract: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is one of the most frequently disrupted tumor suppressors in cancer. The lipid phosphatase activity of PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to repress tumor cell growth and survival. In the nucleus, PTEN promotes chromosome stability and DNA repair. Consequently, loss of PTEN function increases genomic instability. PTEN deficiency is caused by inherited germline mutations, somatic mutations, epigenetic and transcriptional silencing, post-translational modifications, and protein-protein interactions. Given the high frequency of PTEN deficiency across cancer subtypes, therapeutic approaches that exploit PTEN loss-of-function could provide effective treatment strategies. Herein, we discuss therapeutic strategies aimed at cancers with loss of PTEN function, and the challenges involved in treating patients afflicted with such cancers. We review preclinical and clinical findings, and highlight novel strategies under development to target PTENdeficient cancers.

Targeting tumor suppressor p53 for cancer therapy: strategies, challenges and opportunities.

Abstract: p53 is one of the most important tumor suppressor genes that is frequently mutated in human cancers. Generally, p53 functions as a transcription factor that is stabilized and activated by various genotoxic and cellular stress signals, such as DNA damage, hypoxia, oncogene activation and nutrient deprivation, consequently leading to cell cycle arrest, apoptosis, senescence and metabolic adaptation. p53 not only becomes functionally deficient in most cancers, but not infrequently mutant p53 also acquires dominant negative activity and oncogenic properties. p53 has remained an attractive target for cancer therapy. Strategies targeting p53 have been developed including gene therapy to restore p53 function, inhibition of p53-MDM2 interaction, restoration of mutant p53 to wild-type p53, targeting p53 family proteins, eliminating mutant p53, as well as p53-based vaccines. Some of these p53-targeted therapies have entered clinical trials. We discuss the therapeutic potential of p53, with particular focus on the therapeutic strategies to rescue p53 inactivation in human cancers. In addition, we discuss the challenges of p53-targeted therapy and new opportunities for the future.

Pharmacological applications of antioxidants: lights and shadows.

Abstract: 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.

The role of oxidative stress in Huntington's disease: are antioxidants good therapeutic candidates?

Abstract: Huntington’s disease (HD) is the most common polyglutamine neurodegenerative disorder in humans, and is caused by a mutation of an unstable expansion of CAG repeats within the coding region of the HD gene, which expresses the protein huntingtin. Although abnormal protein is ubiquitously expressed throughout the organism, cell degeneration occurs mainly in the brain, and there, predominantly in the striatum and cortex. The mechanisms that account for this selective neuronal death are multifaceted in nature and several lines of evidence suggest that mitochondrial dysfunction, overproduction of reactive oxygen species (ROS) and oxidative stress (an imbalance between pro-oxidant and antioxidant systems resulting in oxidative damage to proteins, lipids and DNA) might play important roles. Over time, this can result in the death of the affected neuronal populations. In this review article we present an overview of the preclinical and clinical studies that have indicated a link between oxidative stress, neurodegeneration, and cell death in HD. We also discuss how changes in ROS production affect neuronal survival, highlighting the evidence for the use of antioxidants including essential fatty acids, coenzyme Q10, and creatine, as potential therapeutic strategies for the treatment of this devastating neurodegenerative disorder.

microRNA-133: Expression, Function and Therapeutic Potential in Muscle Diseases and Cancer

Abstract: microRNAs (miRNAs) are a class of small non-coding RNAs that are 18-25 nucleotides (nt) in length and negatively regulate gene expression post-transcriptionally. miRNAs are known to mediate myriad processes and pathways. While many miRNAs are expressed ubiquitously, some are expressed in a tissue specific manner. miR-133 is one of the most studied and best characterized miRNAs to date. Specifically expressed in muscles, it has been classified as myomiRNAs and is necessary for proper skeletal and cardiac muscle development and function. Genes encoding miR-133 (miR-133a-1, miR-133a-2 and miR-133b) are transcribed as bicistronic transcripts together with miR-1-2, miR-1-1, and miR-206, respectively. However, they exhibit opposing impacts on muscle development. miR-133 gets involved in muscle development by targeting a lot of genes, including SFR, HDAC4, cyclin D2 and so on. Its aberrant expression has been linked to many diseases in skeletal muscle and cardiac muscle such as cardiac hypertrophy, muscular dystrophy, heart failure, cardiac arrhythmia. Beyond the study in muscle, miR-133 has been implicated in cancer and identified as a key factor in cancer development, including bladder cancer, prostate cancer and so on. Much more attention has been drawn to the versatile molecular functions of miR-133, making it a truly valuable therapeutic gene in miRNA-based gene therapy. In this review, we identified and summarized the results of studies of miR-133 with emphasis on its function in human diseases in muscle and cancer, and highlighted its therapeutic value. It might provide researchers a new insight into the biological significance of miR-133.

Human CDC2-Like Kinase 1 (CLK1): A Novel Target for Alzheimer’s Disease

Abstract: The cdc2-like kinases (CLKs) are an evolutionarily conserved group of dual specificity kinases belonging to the CMGC (cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases). The CLK family consists of four isoforms namely CLK1, CLK2, CLK3 and CLK4. The human CLK1 encoded protein comprises 454 amino acids and the catalytic domain of CLK1 exhibits the typical protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phosphorylate exogenous substrates on serine and threonine residues. CLK1 plays an important role in the regulation of RNA splicing through phosphorylation of members of the serine and arginine-rich (SR) family of splicing factors. CLK1 is involved in the pathophysiology of Alzheimer's disease by phosphorylating the serine residue in SR proteins. Nuclear speckles of the nucleoplasm contain the stored form of SR proteins and are moderately responsible for the choice of splicing sites during pre-mRNA splicing. Hence, the inhibition of CLK1 can be used as a therapeutic strategy for Alzheimer's disease. Many natural and synthetic molecules are reported to possess CLK1 inhibitory activity. Some specific examples are Marine alkaloid Leucettamine B and KH-CB19. Leucettamine B is a potent inhibitor of CLK1 (15 nM), Dyrk1A (40 nM), and Dyrk2 (35 nM) and a moderate inhibitor of CLK3 (4.5 µM) whereas KH-CB19 is a highly specific and potent inhibitor of the CLK1/CLK4. X-ray crystallographic studies have revealed the binding mode of marine sponge metabolite hymenialdisine and a dichloroindolyl enamino nitrile (KH-CB19) to CLK1. This review focuses on the role of CLKs in the pathophysiology of Alzheimer's disease and therapeutic potential of targeting CLK1 in Alzheimer's disease drug discovery and development. In addition, the recent developments in drug discovery efforts targeting human CLK1 are also highlighted.

Targeting Tumor Suppressor Networks for Cancer Therapeutics

Abstract: Cancer is a consequence of mutations in genes that control cell proliferation, differentiation and cellular homeostasis. These genes are classified into two categories: oncogenes and tumor suppressor genes. Together, overexpression of oncogenes and loss of tumor suppressors are the dominant driving forces for tumorigenesis. Hence, targeting oncogenes and tumor suppressors hold tremendous therapeutic potential for cancer treatment. In the last decade, the predominant cancer drug discovery strategy has relied on a traditional reductionist approach of dissecting molecular signaling pathways and designing inhibitors for the selected oncogenic targets. Remarkable therapies have been developed using this approach; however, targeting oncogenes is only part of the picture. Our understanding of the importance of tumor suppressors in preventing tumorigenesis has also advanced significantly and provides a new therapeutic window of opportunity. Given that tumor suppressors are frequently mutated, deleted, or silenced with loss-of-function, restoring their normal functions to treat cancer holds tremendous therapeutic potential. With the rapid expansion in our knowledge of cancer over the last several decades, developing effective anticancer regimens against tumor suppressor pathways has never been more promising. In this article, we will review the concept of tumor suppression, and outline the major therapeutic strategies and challenges of targeting tumor suppressor networks for cancer therapeutics.

Therapeutic modulation of gut microbiota: current clinical applications and future perspectives.

Abstract: Human beings and gut microbiota are in a symbiotic relationship, and the hypothesis of a “super organism” composed of the human organism and microbes has been recently proposed. The gut microbiota fulfills important metabolic and immunological tasks, and the impairment of its composition might alter homeostasis and lead to the development of microbiota-related diseases. The most common illnesses associated with alterations of the gut microbiota include inflammatory bowel disease, gastroenteric infections, irritable bowel syndrome and other gastrointestinal functional diseases, colorectal cancer, metabolic syndrome and obesity, liver diseases, allergic diseases, and neurological diseases such as autism. In theory, every disease associated with the impairment of intestinal microflora might benefit from the therapeutic modulation of the gut microbiota. A number of attempts to manipulate the microbiota have not produced identical results for every disease. Although antibiotics and probiotics have been available for a long time, the so-called fecal microbiota transplantation, which is a very old remedy, was only recently re-evaluated as a promising therapeutic approach for microbiota impairment. A comprehensive understanding of the gut microbiota composition, in states of both health and various diseases, is needed for the development of future approaches for microbiota modulation and for developing targeted therapies. In this review, we describe the role of the microbiota in several diseases and the related treatment options that are currently available.

The first approved agent in the Glitazar's Class: Saroglitazar.

Abstract: The new chemical entity (NCE) has been knocked as novel antidiabetic agent, e.g. Saroglitazar. Saroglitazar is a drug for the treatment of Type II diabetes. Saroglitazar is marketed under the trade name Lipaglyn, developed by the Zydus Cadila. Lipaglyn is the first indigenously developed NCE by any Indian pharmaceutical company, ever. Lipaglyn has been approved for the treatment of Type II diabetes by the Drug Controller General of India in June 2013. Lipaglyn is indicated for the patients suffering from diabetes dyslipidemia. It also provides the option of a once-daily oral therapy. Saroglitazar regulates the lipid parameters as well as glycemic control. The present article describes Saroglitazar with its chemical synthesis and patent status with its summary of clinical studies.

Na + /K + ATPase Inhibitors in Cancer

Abstract: Sodium potassium pump (Na(+)/K(+) ATPase) is a transmembrane protein complex found in all higher eukaryotes acting as a key energy-consuming pump maintaining ionic and osmotic balance in cells. Recently recognized as an important transducer and/or integrator of various signals as well as a protein-protein interaction scaffold forming receptor complexes with signaling properties, the most prominent pharmacological role of Na(+)/K(+) ATPase inhibitors is the increase of myocardial contractility in pathologic conditions such as congestive heart failure. Consequently, modulators of Na(+)/K(+) ATPase such as digoxin have been approved by regulatory authorities and are widely used in the treatment of cardiac failure since 1975. Initiating from early observations of reduction of cancer incidence in cardiac patients taking digoxin, recent epidemiological and other studies have consolidated the anti-cancer potential of Na(+)/K(+) ATPase inhibitors in indications such as prostate, breast, lung cancer or leukemia. More importantly, a new series of pharmacologically optimized Na(+)/K(+) ATPase inhibitors has recently shown strong anti-cancer activities in multiple preclinical assays and have reached early clinical trials. Altogether, these results suggest that Na(+)/K(+) ATPase is an emerging cancer target that merits further investigation. In this review, we summarize key functional properties of the enzyme that are highly relevant for cancer cell selectivity, review the most prominent chemical classes of Na(+)/K(+) ATPase inhibitors and analyze their downstream effectors. Moreover, we discuss overall development prospects of these candidate drugs on their way to becoming new effective treatments of cancer in patients.

Oxidative stress: meeting multiple targets in pathogenesis of diabetic nephropathy.

Abstract: Excessive production of reactive oxygen species is an important mechanism underlying the pathogenesis of diabetes associated macrovascular and microvascular complications including diabetic nephropathy. Diabetic nephropathy is characterized by glomerular enlargement, early albuminuria and progressive glomerulosclerosis. The pathogenesis of diabetic nephropathy is multi-factorial and the precise mechanisms are unclear. Hyperglycemia-mediated dysregulation of various pathways either enhances the intensity of oxidative stress or these pathways are affected by oxidative stress. Thus, oxidative stress has been considered as a central mediator in progression of nephropathy in patients with diabetes. In this review, we have focused on current perspectives in oxidative stress signaling to determine common biological processes whereby diabetes-induced oxidative stress plays a central role in progression of diabetic nephropathy.

Sex differences in oxidative stress biomarkers.

Abstract: Although an increased oxidative stress has been associated with several pathologies, predictive value of circulating oxidative stress biomarkers remains poorly understood. It has been demonstrated that several pathologies underestimated in women, including cardiovascular diseases, develop differently by gender. In this study, conducted on 195 healthy volunteers, we assessed the putative gender difference in prooxidant and antioxidant status. Our results were successful in demonstrating a significant difference in oxidative stress between sexes, whereas no difference was found in the plasma antioxidant barrier efficiency. To assess whether this difference was due to hormonal status (i.e. estrogen levels), female samples were divided into pre-menopausal and post-menopausal groups. No significant difference emerged for both biomarkers. Despite the well-known antioxidant estrogen role, women in this study presented a higher oxidative status than males. This suggests that there is a difference in the production and metabolic deactivation of reactive oxygen metabolite.

COX-2 signaling and cancer: new players in old arena.

Abstract: Cancer is a leading cause of death worldwide. The expression of COX-2 and prostaglandins has not only been associated with various types of cancer but is also directly proportional to their aggressiveness including metastasis. Thus, inhibition of COX-2 activity has been one of the preferred targets for cancer reduction. Broad spectrum inhibition of all forms of COX (using NSAIDs) is associated with various side effects ranging from gastric ulceration to renal problems. Even specific COX-2 inhibitors (COXIBs) are associated with side effects like myocardial infarction. Alternative strategies including siRNA technology are also not very victorious due to their off-target associated problems. Thus, there is an urgent need for the development of strategies where COX-2 activity may be reduced without inducing any side effects. One of the approaches for designing novel inhibitors may be to target various molecules downstream of COX-2. In this review, we have tried to cover the basic biology of COX-2 and its association with different types of cancer. Various generations of COX-2 inhibitors have been covered with their merits and demerits. Possible exploitation of novel targets like EP receptors, mPGES and various other downstream molecules which can be utilized for a better COX-2 signaling inhibition and thus efficient cancer reduction with minimal side effects has been discussed.

The role of STAT3 signaling in mediating tumor resistance to cancer therapy.

Abstract: Signal transducer and activator of transcription 3 (STAT3) is activated in many cancer types and can regulate pathways involving tumorigenesis, cell proliferation, cell survival and angiogenesis. Upstream cytokine signaling through multiple trans-membrane receptors can enhance the activation of STAT3 and promote tumor progression. Importantly, STAT3 activation can also be induced via the Janus-activated kinase 1/2 (JAK1/2) and Src family kinases. Target-specific drug therapies have been developed to inhibit many of the upstream receptor and non-receptor activators of STAT3 and are now approved for clinical use. Recently, resistance to standard-of-care therapies has been linked to constitutive or unabated STAT3 activation, suggesting that combination therapy with STAT3 inhibitors may be of clinical benefit. Furthermore, STAT3 activity has also been shown to regulate self-renewal of cancer stem cells that are often refractory to chemotherapy treatment. This review will focus on STAT3 mediated resistance to cancer therapy and discuss strategies to overcome this resistance.

Can trehalose prevent neurodegeneration? Insights from experimental studies.

Abstract: Inappropriate protein aggregation is a key mechanism in the pathogenesis of several neurodegenerative disorders. One of the main strategies by which cells deal with abnormal protein aggregates is autophagy, a degradation pathway for intracellular aggregate-prone proteins. Trehalose, a non-reducing disaccharide which has been utilized extensively in the food industry, has been recently demonstrated to have a number of unique properties that point to its potential utility in preventing neurodegeneration. First, trehalose may act as a potent stabilizer of proteins and is able to preserve protein structural integrity. Second, it is a chaperone and reduces aggregation of pathologically misfolded proteins. Third, it improves the clearance of the mutant proteins which act as autophagy substrates when aberrant protein deposition occurs. Notably, trehalose is an mTOR-independent inducer of autophagy, and in animal models of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Huntington's disease, has been shown to decrease the levels of toxic protein aggregates, increase autophagy, and improve clinical symptoms and survival. In summary, mounting experimental evidence suggests that trehalose may prevent neurodegenerative disorders by stabilizing proteins and promoting autophagy. Because of the low toxicity profile that allows for administration for extended periods, human studies of trehalose in preventing neurodegeneration are warranted.

Inducible nitric oxide synthase as a possible target in hypertension.

Abstract: Nitric oxide (NO) is an important vasodilator produced by vascular endothelium. Its enzymatic formation is derived from three different synthases: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) synthases. While relatively small amounts of NO produced by eNOS are important to cardiovascular homeostasis, high NO levels produced associated with iNOS activity may have detrimental consequences to the cardiovascular system and contribute to hypertension. In this article, we reviewed current literature and found mounting evidence indicating that increased iNOS expression and activity contribute to the pathogenesis of hypertension and its complications. Excessive amounts of NO produced by iNOS up-regulation can react with superoxide anions forming peroxynitrite, thereby promoting nitrosative stress and endothelial dysfunction. In addition, abnormal iNOS activity can up-regulate arginase activity, allowing it to compete with eNOS for L-arginine, thereby resulting in reduced NO bioavailability. This may also lead to eNOS uncoupling with enhanced production of superoxide anions instead of NO. All these alterations mediated by iNOS apparently contribute to hypertension and its complications. We also reviewed current evidence showing the effects of iNOS inhibitors on different animal models of hypertension. iNOS inhibition apparently exerts antihypertensive effects, decreases oxidative and nitrosative stress, and improves vascular function. Together, these studies highlight the possibility that iNOS is a potential pharmacological target in hypertension.

Rac-1 as a New Therapeutic Target in Cerebro- and Cardio-Vascular Diseases

Abstract: 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.

New Use for Old Drugs? Prospective Targets of Chloroquines in Cancer Therapy

Abstract: During the last decade research is gradually repositioning the antimalarial drug chloroquine, and certain related quinoline derivatives, as anticancer agents. Chloroquine and hydroxychloroquine, in particular, have relatively well-characterized toxicity profiles due to several decades of use for treatment of malaria. Previously published review articles provide an excellent overview of the diversity of chloroquine effects on cancer cells, both in the cell culture as well as on human tumors grafted into mice; and an account of the increasing pace of incorporation of hydroxychloroquine in combination treatment schemes for clinical studies. In this review we present some features that are common between cancers that are sensitive to quinoline derivatives, in particular features that are amenable to pharmaceutical intervention.

The Role of P2Y 12 Receptor and Activated Platelets During Inflammation

Abstract: Platelets play an important role not only during thrombosis, but also in modulating immune responses through their interaction with immune cells and by releasing inflammatory mediators upon activation. The P2Y 12 receptor is a Gicoupled receptor that not only regulates ADP-induced aggregation but can also dramatically potentiate secretion, when platelets are activated by other stimuli. Considering the importance of P2Y 12 receptor in platelet function, a class of antiplatelet drugs, thienopyridines, have been designed and successfully used to prevent thrombosis. This review will focus on the role of activated platelets in inflammation and the effects that P2Y 12 antagonism exerts on the inflammatory process. A change in platelet functions was noted in patients treated with thienopyridines during inflammatory conditions, suggesting that platelets may modulate the inflammatory response. Further experiments in a variety of animal models of diseases, such as sepsis, rheumatoid arthritis, myocardial infarction, pancreatitis and pulmonary inflammation have also demonstrated that activated platelets influence the inflammatory state. Platelets can secrete inflammatory modulators in a P2Y 12 –dependent manner, and, as a result, directly alter the inflammatory response. P2Y 12 receptor may also be expressed in other cells of the immune system, indicating that thienopyridines could directly influence the immune system rather than only through platelets. Overall the results obtained to date strongly support the notion that activated platelets significantly contribute to the inflammatory process and that antagonizing P2Y 12 receptor can influence the immune response.

Exploiting APC Function as a Novel Cancer Therapy

Abstract: The Adenomatous Polyposis Coli (APC) tumor suppressor is most commonly mutated in colorectal cancers such as familial adenomatous polyposis (FAP); as well as many other epithelial cancers like breast, pancreatic, and lung cancer. APC mutations usually result in a truncated form of the protein lacking the carboxy-terminal region resulting in loss of function. Mutations in APC have been identified in early stages of cancer development making it a gatekeeper of tumor progression and therefore an ideal therapeutic target. APC is best known for its role as a negative regulator of the Wnt/β -catenin pathway. However, APC also mediates several other normal cell functions independently of Wnt/β-catenin signaling such as apical-basal polarity, microtubule networks, cell cycle, DNA replication and repair, apoptosis, and cell migration. Given the vast cellular processes involving APC, the loss of these "normal" functions due to mutation can contribute to chemotherapeutic resistance. Several therapeutic treatments have been explored to restore APC function including the reintroduction of APC into mutant cells, inhibiting pathways activated by the loss of APC, and targeting APCmutant cells for apoptosis. This review will discuss the normal functions of APC as they relate to potential treatments for patients, the role of APC loss in several types of epithelial cancers, and an overview of therapeutic options targeting both the Wnt-dependent and -independent functions of APC.

Targeting the LKB1 Tumor Suppressor

Abstract: LKB1 (also known as serine-threonine kinase 11, STK11) is a tumor suppressor, which is mutated or deleted in Peutz-Jeghers syndrome (PJS) and in a variety of cancers. Physiologically, LKB1 possesses multiple cellular functions in the regulation of cell bioenergetics metabolism, cell cycle arrest, embryo development, cell polarity, and apoptosis. New studies demonstrated that LKB1 may also play a role in the maintenance of function and dynamics of hematopoietic stem cells. Over the past years, personalized therapy targeting specific genetic aberrations has attracted intense interests. Within this review, several agents with potential activity against aberrant LKB1 signaling have been discussed. Potential strategies and challenges in targeting LKB1 inactivation are also considered.

Microneedle-based drug delivery systems for transdermal route.

Abstract: Transdermal delivery offers an attractive, noninvasive administration route but it is limited by the skin's barrier to penetration. Minimally invasive techniques, such as the use of microneedles (MNs), bypass the stratum corneum (SC) barrier to permit the drug's direct access to the viable epidermis. These novel micro devices have been developed to puncture the skin for the transdermal delivery of hydrophilic drugs and macromolecules, including peptides, DNA and other molecules, that would otherwise have difficulty passing the outermost layer of the skin, the SC. Using the tools of the microelectronics industry, MNs have been fabricated with a range of sizes, shapes and materials. MNs have been shown to be robust enough to penetrate the skin and dramatically increase the skin permeability of several drugs. Moreover, MNs have reduced needle insertion pain and tissue trauma and provided controlled delivery across the skin. This review focuses on the current state of the art in the transdermal delivery of drugs using various types of MNs and developments in the field of microscale devices, as well as examples of their uses and clinical safety.

Phosphorothioate oligonucleotides: effectiveness and toxicity.

Abstract: Background: Many experimental and clinical studies have focused on the antisense strategy. In this context phosphorothioate oligonucleotides are compounds addressed to hybridize to a targeted mRNA inducing a variety of effects including inhibition of the expression of proteins involved in different pathological processes and preventing translation. Methods: In this review, we provide an update on clinical efficacy and toxicological profile of phosphorothioate oligonucleotides used in experimental and clinical studies, also focusing on the use of the antisense strategy in the context of Duchenne muscular dystrophy which is a key pathology to study different aspects of this therapy. Pubmed/Medline was searched using the keyword “Phosphorotioate” combined with “Antisense”, “Oligonucleotide” and “Duchenne muscular dystrophy”. Conclusions: Phosphorothioate oligonucleotide transient activation of the complement cascade represents the most evident toxicological response, as showed by in vivo studies. It is also known that many of these compounds induce a prolongation of activated partial thromboplastin time, a reaction which is often highly transient and proportional to the oligonucleotide plasma concentrations, making that effect clinically insignificant for the current treatment regimens. In summary, current evidence shows limited untoward effects and reversibility of the damage induced, at least for some of those compounds, with promising effectiveness for treatment of various pathologies.

MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance.

Abstract: p53 is one of the main regulators of apoptosis, senescence, cell cycle arrest and DNA repair. The expression, function and stabilization of p53 are governed by a complex network of regulators including p14(ARF) and MDM2. MDM2 is the main negative regulator of p53 activity and stability. Unlike tumours in adults, which tend to overcome p53 regulation by p53 mutations, the paediatric tumours neuroblastoma and sarcoma frequently retain wild type p53. Nevertheless, in childhood cancer the p53 pathway is commonly impaired due to upstream MDM2-p14(ARF)-p53 network aberrations. In contrast, aberrations of the p53 downstream pathway are very rare. In cancer cells with intact p53 downstream function MDM2 inhibition, and subsequent rapid increases in nuclear p53 levels, potently "re-activate" dormant apoptotic pathways and rapidly induce apoptotic cell death. As a result MDM2-p53 interaction inhibitors, including cis-imidazolines analogs (Nutlins), are potentially very effective agents in neuroblastoma and sarcomas. Predictive biomarkers are important as a lack of p53 mutations appears to reliably predict response to these inhibitors. Tumours should be screened for p53 mutations in children considered for MDM2-p53 interaction inhibitors. In addition, it is essential that other predictive biomarkers are investigated. The serum concentration of macrophage inhibitory cytokine- 1 (MIC-1) may be a good pharmacodynamic biomarker based on recent findings. In conclusion, targeting the interaction between p53 and its main negative regulator MDM2 represents a major new therapeutic approach in poor prognosis paediatric malignancies without p53 mutations.

Hsp27 as a therapeutic target in cancers.

Abstract: Heat shock protein 27 (Hsp27), induced by heat shock, environmental and pathophysiological stressors, is a multidimensional protein that acts as a protein chaperone and an antioxidant. This protein plays a major role in the inhibition of apoptosis and actin cytoskeletal remodeling. This stress-activated protein is up-regulated in many cancers and is associated with poor prognosis as well as treatment resistance by protecting cells from therapeutic agent that normally induces apoptosis. This review highlights the most recent findings and role of Hsp27 in cancer and the different strategies to target and inhibit Hsp27 for clinical purposes.

Catching the therapeutic window of opportunity in early Crohn's disease.

Abstract: Crohn's disease (CD) is a chronic, disabling, progressive and destructive disease. The general goal of conventional step-up strategy in CD treatment is to treat and control symptoms. This strategy did not change the disease course and is now being replaced with a treat-to-target approach. Achieving deep remission (clinical remission and absence of mucosal ulcerations) is the target in CD in 2014. Inducing and maintaining deep remission is needed to prevent long-term outcomes such as bowel damage and disability in CD. Diagnostic delay is a common issue in CD and is associated with an increased risk of bowel damage over time. Identification of poor prognostic factors, risk stratification together with the development of "red flags" may result in early intervention with disease-modifying agents such as anti-TNF agents with the final aim of preventing overtreatment and avoiding undertreatment. Similar to rheumatoid arthritis, by catching the therapeutic window of opportunity in early CD and achieving deep remission, this could be the best way to change disease course (hospitalizations, surgeries, bowel damage, and disability) and patients' life.

Impact of matrix metalloproteinases on atherosclerosis.

Abstract: Atherosclerosis is now widely recognized as a chronic inflammatory disease that involves innate and adaptive immune responses. Both cellular and humoral components of the immune system have been implicated in atherogenesis. Growing evidence suggests that immune cells play crucial roles in atherogenic plaque formation. Vulnerability of the plaque probably plays an important role in rupture. Most ruptures occur at the periphery of the fibrous cap that covers the lipid-rich core-points where the cap is usually thinnest and most heavily infiltrated by macrophage foam cells. Sudden rupture of a plaque triggers unstable angina, acute myocardial infarction, and sudden cardiac death. Initiation of collagen breakdown in plaques requires matrix metalloproteinase (MMP) family members including MMP-1, MMP-8, and MMP- 13. In addition, other MMPs such as MMP-2, -3, -9, -10 and -12 have also been reported to play roles in atherosclerosis. This review aims to focus on description of general structural features of MMPs and their roles in atherosclerosis.

Mitochondrial pathology in osteoarthritic chondrocytes.

Abstract: Osteoarthritis (OA) is a chronic degenerative disease leading to aberrance of cartilage structures with unclear or multifactorial mechanisms. Recently, a great portion of research endeavor to explore the molecular mechanisms of OA in focusing on the mitochondrial pathology. Mitochondrial respiratory chain (MRC) produces reactive oxygen species (ROS), which in turn impair mtDNA integrity and link to cartilage degradation in OA. The fine-tuning between ROS and antioxidant within chondrocytes ensures cartilage homeostasis. With disturbance from pro-inflammatory cytokines, oxidative stress synergistically instigates cellular signaling and exacerbates mitochondrial pathology, which may affect several pathways implicated in OA cartilage degradation, including oxidative stress, increase of cytokine-induced chondrocytes inflammation and matrix catabolism, aging and senescence, obesity-related pathology, and cartilage matrix calcification. Unveiling the molecular mechanisms of mitochondrial function in OA pathogenesis and progression is essential for providing relevant therapeutic targets. These suggest that efficient protection and improvement of mitochondrial activity can be a therapeutic alternative for OA patients.

EGFR as a Potential Target for the Treatment of Pancreatic Cancer: Dilemma and Controversies

Abstract: Pancreatic Ductal Adenocarcinoma (PDAC) is among the most lethal solid tumors with grim prognosis. This dismal outcome can partially be explained by the resistance to currently available chemotherapy regimens or the failure of most anticancer agents, which prompted the development of new and effective therapeutic-approaches, such as inhibitors of the epidermal growth factor receptor (EGFR). Some of these EGFR inhibitors (e.g., erlotinib) are approved for lungcancer, however available data are inconclusive for treatment of pancreatic cancer patients with EGFR-targeted-therapies. Here we describe the critical role of EGFR pathway in pancreatic-cancer, strategies to enhance the effectiveness of EGFRinhibitors as well as the preclinical/clinical studies with particular emphasis on recent findings with monoclonal antibodies and tyrosine-inhibitors. Several combinations of EGFR inhibitors with other agents illustrate inhibition of tumor-induced angiogenesis and cell growth. Moreover, combination of erlotinib with gemcitabine showed statistically significance in overall-survival, compared to gemcitabine-alone. However high cost, little survival gain and increased risk of toxicities have limited its efficacy. Considering the multiple genetic mutations and the crosstalk of signaling pathways, (1) development of multiple targeted-therapies; (2) identification of predictive-biomarkers; and (3) those patients who are most likely benefit from therapy, could provide valuable direction for the clinical development of EGFR inhibitors. Moreover further preclinical/clinical studies are warranted to identify determinants of the activity of EGFR-inhibitors and mechanisms leading to resistance to EGFR inhibitors, through the analysis of genetic and environmental alterations affecting EGFR and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivity of current anticancer strategies targeting EGFR in pancreatic cancer.

Proteomic profiling of a biomimetic drug delivery platform

Abstract: Current delivery platforms are typically designed for prolonged circulation that favors superior accumulation of the payload in the targeted tissue. The design of efficient surface modifications determines both a longer circulation time and targeting abilities of particles. The optimization of synthesis protocols to efficiently combine targeting molecules and elements that allow for an increased circulation time can be challenging and almost impossible when several functional elements are needed. On the other hand, in the last decade, the development of bioinspired technologies was proposed as a new approach with which to increase particle safety, biocompatibility and targeting, while maintaining the synthesis protocols simple and reproducible. Recently, we developed a new drug delivery system inspired by the biology of immune cells called leukolike vector (LLV) and formed by a nanoporous silicon core and a shell derived from the leucocyte cell membrane. The goal of this study is to investigate the protein content of the LLV. Here we report the proteomic profiling of the LLV and demonstrate that our approach can be used to modify the surface of synthetic particles with more than 150 leukocyte membrane associated proteins that determine particle safety, circulation time and targeting abilities towards inflamed endothelium.