Current Medicinal Chemistry - Volume 15, Issue 9, 2008

Stat-3 (Signal Transduction and Activator of Transcription) is a member of the Stat family of latent, cytosolic transcription factors that directly relate signals from the plasma membrane to the nucleus. This protein is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human tumors, and it has been identified as a promising target for cancer drug discovery. This review deals with the recent developments of peptides and peptidomimetics or even non-peptidic small molecules, able to bind to the SH2 domain of Stat-3, thus blocking its functions. Moreover, several compounds able to alter the Stat-3 pathway by inhibition of kinases upstream to Stat-3, or even with unknown targets, were reviewed.

The potential for carotenoids to modulate chronic diseases related to smoke is currently under investigation and renewed interest has been placed on achieving a better understanding of the mechanism(s) of action of carotenoids in smoke-exposed biological systems. Available data currently show that, while carotenoids alone are not harmful, their interaction with smoke may shift from beneficial to detrimental depending on the dose, the type of carotenoid as well as the biological environment in which they act. Several mechanisms have been proposed to explain such a shift. They include: (i) changes in cell oxidative status, which tips the β-carotene antioxidantprooxidant balance toward a prooxidant status; (ii) modulation of the levels of key proteins involved in the regulation of cell proliferation and apoptosis; (iii) reduction of retinoic acid signal pathway which down-regulates the RARβ expression and up-regulates AP-1; (iv) interference with absorption of other nutrients at better antioxidant profile; (v) formation of specific carotenoid oxidation products. This review summarizes the available evidences in cultured cells, animal models and humans for a modulatory action of carotenoids on the dangerous effects of smoke and focuses on the main molecular pathways involved in this process.

Malignant mesothelioma is a highly invasive tumor originating from the mesothelial linings of the pleura, peritoneum and pericardium. It is seldom amenable to surgical intervention and poorly responsive to radiotherapy, leaving chemotherapy as the main therapeutic option for most patients. The development of effective drug regimens against mesothelioma has proven extremely difficult and a standard first-line treatment for patients with unresectable tumors has not been established until recently. Despite the benefits obtained with this newly validated standard of care, which is based on the combination of pemetrexed and cisplatin, the prognosis for mesothelioma patients remains poor, median survival is still less than two years and more active treatments are urgently needed. This article will focus on the molecular basis providing the rationale for targeted interventions against mesothelioma and will review targeted agents under evaluation as new potential therapeutic options for mesothelioma patients. Such agents include inhibitors of growth factor receptors, ligands and intracellular effectors. The agents targeting vascular endothelial growth factor signaling are of particular interest, due to the involvement of this pathway both in tumor angiogenesis and autocrine stimulation of mesothelioma cell growth. Alternative approaches are based on inhibitors of the ubiquitin-proteasome pathway and of histone deacetylases which, notwithstanding the functional divergence of the corresponding targets, share the ability to determine a wide modulation of the cancer cell phenotype that can lead to cell cycle arrest, apoptosis and sensitization to different antineoplastic treatments. A recombinant immunotoxin targeted to the membrane antigen mesothelin is an additional agent whose activity is being evaluated in mesothelioma patients.

It is almost 70 years since the discovery by Huggins et al. that androgens are essential for prostate cancer (PC) growth and progression, and there has been about 30 years experience using ketoconazole for PC theraphy. Since then we have come a long way in learning about the disease and developing new strategies to approach it, among which is cytochrome 17α-hydroxylase-C17,20-lyase (CYP17) inhibition. This review focuses on the efforts to find prospective CYP17 inhibitors, both steroidal and nonsteroidal, in the absence of a 3D structure of the enzyme. It covers almost 4 decades of literature with highlights on the most significant achievements in this area, providing insight into PC pathophysiology, management and treatment options.

Treatment of human herpes simplex virus (HSV) diseases represents an important goal, as herpetic infections are not controlled by vaccination. Many therapeutic agents have been developed and used for HSV infections and several alternative natural compounds are under investigation. Most of the drugs clinically employed against HSV types 1 and 2 are represented by guanosine nucleoside analogues, such as aciclovir and aciclovir-like drugs. The emergence of aciclovir-resistant virus strains provided a stimulus for increased search of new effective agents. Alternative drugs are other nucleoside analogues, such as the vidarabine, brivudin, and cidofovir, or pyrophosphate analogues such as foscarnet, that showed efficacy for HSV infections refractory to aciclovir. However, the risk of adverse effects reported for available anti-herpetic compounds and the frequent development of drug-resistant strains of HSV following therapeutic treatment generate the need for new antiviral agents. In the last years, several studies have been carried out on the anti- HSV activity of different components of innate host defences such as cationic antimicrobial peptides. The antiviral activity of these peptides often appears to be related to the viral adsorption and entry process or is a result of a direct effect on the viral envelope. Other natural compounds, extracts from medicinal plants employed in ethnomedicine and displaying marked anti-herpetic activity, are at present under investigation to determine the scientific evidence and rationale for their clinical use. This review discusses the anti-HSV activity of compounds licensed for clinical use and promising natural molecules.

Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are fatal neurodegenerative disorders. An abnormal isoform of the prion protein (PrPSc) generated by post-translational modification of the cellular prion protein (PrPC) is believed to be the main component of this infectious agent. PrPSc is relatively resistant to proteinase K (PK) digestion. This characteristic has been widely accepted as the physicochemical basis for distinguishing between PrPC and PrPSc. PrPC is a glycoprotein that contains 2 Asnlinked glycosylation sites; it is present in the cells in 3 different glycoforms, including an unglycosylated form. Hence, for different prion strains, PrPSc exhibits different glycoform patterns with different ratios of the 3 forms by western blot. Recently, phenotypes of TSEs have emerged that exhibit PrPSc with different glycoform patterns and/or mild PK resistance in comparison with previously described typical cases. Regarding sheep scrapie, atypical scrapie cases that are represented by Nor98 have been reported among sheep previously presumed to be genetically scrapie-resistant. Moreover, atypical bovine spongiform encephalopathy (BSE) cases have been reported. These are classified into 2 phenotypes (H-type and L-type) based on the molecular weight of unglycosylated band of PK-digested PrPSc. The origin of these emerging prion diseases is obscure, conformational differences of PrPSc may cause the different biological and biochemical characteristics of prion strains.

It has been known for a long time that inhaled adenosine-monophosphate (AMP) induces airway obstruction in asthmatic patients, but not in healthy subjects. The mechanism of AMP is indirect and occurs via its decay product, adenosine. It stimulates mast cells through its low-affinity receptor A2B to release histamine, which ultimately leads to smooth muscle contraction. This feature of adenosine reveals its pro-inflammatory function, which may play important role in asthma. Indeed, mice lacking adenosine deaminase (ADA), an enzyme which decomposes adenosine, develop asthma-like disorder with elevated IgE, eosinophilia and airway hyperresponsiveness. Human studies showed elevated adenosine levels in bronchoalveolar lavage and exhaled breath condensate of asthmatics as compared to healthy people. Furthermore, certain human ADA phenotypes are associated with prevalence of asthma. These data suggest a protective role for ADA and a pro-inflammatory function for adenosine in asthma. The role of adenosine in inflammatory processes, however, is not unequivocal. Some in vitro studies showed that adenosine binding to its high-affinity receptor A2A results in inhibition of leukotriene synthesis or function of adhesion molecules. It is possible that the concentration of adenosine in lung tissues determines whether it promotes or reduces inflammation. Adenosine has also been associated with other respiratory diseases such as fibrosis, sarcoidosis, cystic fibrosis or tuberculosis. Identification of adenosine receptor subtypes and their role in the pathomechanism of respiratory diseases may provide new therapeutical targets. This review aims to summarize the role of adenosine and adenosine receptors in asthma and other pulmonary disorders.

The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is responsible for the degradation of fibrin into soluble degradation products. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). There are 3 types of PAIs described so far but the most important fibrinolytic inhibitor in vivo is PAI type 1 (PAI-1). Among others, the presence of metabolic syndrome and the -675 4G/5G promoter polymorphism are known to be modulators of PAI-1 levels. Besides their fibrinolytic profile, plasmin and plasminogen activators are implicated in tissue proliferation and cellular adhesion, as they can proteolytically degrade the extracellular matrix and regulate the activation of both growth factors and matrix metalloproteinases. By all these means, the fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis and cancer. PAI-1 has been studied in different settings with thrombotic pathophysiology, such as coronary artery disease and ischaemic stroke. Controversial results have been published and concerns about study designs or presence of confounders have been claimed to be responsible of them. Recently, its involvement in adverse thrombotic events related to the modern drug-eluting coronary stents has renewed the interest of its study. PAI-1 also plays an important role in signal transduction, cell adherence, and migration. Indeed, studies of several types of cancers, including breast cancer, have shown that increased uPA and PAI-1 levels are associated with aggressive tumor behavior and poor prognosis. Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus with marked ability to attach and invade the peritoneum. It is one of the most frequent benign gynecological diseases that affect women with pelvic pain or infertility during their reproductive age. Immune system disorders, genetic predisposition, altered peritoneal environment and endometrial alterations are believed to increase the susceptibility to endometriosis. The plasminogen activator system may be involved in this process, where local extracellular proteolysis plays a crucial role. Altered expression of several components of the fibrinolytic system in both eutopic and ectopic endometrium and peritoneal fluid of women with the disease has been implicated not only in the onset, but also in the progression of the endometriotic lesions.

Chronic hepatitis B virus (HBV) infection has a variable course leading to cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis and clinical outcome of HBV infection are strictly dependent on both viral factors, such as life cycle and genotypic variants, and host immune response (i.e. viral persistence). Although therapy of hepatitis B is evolving, which between single and/or combined agents are most effective, how long therapy should last, which criteria should be used to start or continue and switch or stop therapy are to be defined. Two major groups of therapies are currently utilized for chronic hepatitis: immunomodulatory (interferons) and antivirals (nucleoside and nucleotide analogues), all with their own advantages and limitations. In fact, the development of specific antiviral therapies has provoked the appearance of a relevant problem: drug resistances. The emerged antiviral drug-resistant strains of HBV leads to a poor prognosis for infected patients. Thus, many basic and clinical research challenges remain in defining optimal means of management of viral hepatitis B and its related liver diseases. This paper provides a review of new available and developing treatment options for HBV associated liver diseases. In the near future the most realistic therapeutic option for the majority of patients with HBV infection will be combination and/or long-term use of new and stronger antiviral drugs, if they maintain good safety profiles, achieve low resistance rates and will be available at lower prices.