Current Pharmaceutical Design - Volume 18, Issue 26, 2012

The Editorial Board wishes to dedicate this issue of Current Pharmaceutical Design to the founding Executive Editor of the journal, Prof. Dr. Atta-ur-Rahman, FRS, on his 70th birthday. The Editorial Board acknowledges the tremendous achievements of Prof. Rahman in the fields of Organic Chemistry in general and on bioactive natural products in particular. Prof. Rahman's honors include: the first scientist from the Muslim world to have won the prestigious UNESCO Science Prize (1999) in the 35 year old history of the Prize; elected as Fellow of Royal Society (London) in July 2006; conferred honorary doctorate degrees from many prestigious universities, including the University of Cambridge. On a national level his services are acknowledged in the form of four prestigious civil awards, including these highest national awards: Nishan-e-Imtiaz (2002), Hilal-e-Imtiaz (1998), Sitara-e-Imtiaz (1991) and Tamgha-e- Imtiaz (1983). At an academic level, Prof. Rahman has 856 publications in several fields of organic chemistry including 658 research publications, 21 patents, 113 books and 65 chapters in books published largely by major U.S. and European presses. He is currently the Editor-in-Chief of 12 scientific journals in fields ranging from Medicinal Chemistry to Pharmaceutical Drug Design. Seventy six students have completed their Ph.D. degrees under his supervision. He chairs the Network of Academies of Sciences of Islamic Countries (NASIC) and is the Vice-President (Central & South Asia) of the Academy of Sciences for the Developing World (TWAS) Council, and Foreign Fellow of Korean Academy of Sciences. Prof. Atta-ur-Rahman was the President of the Pakistan Academy of Sciences (2003-2006) and was again elected as the President of the Academy from 1st of January 2011. In particular, Prof. Rahman has made outstanding contribution to Current Pharmaceutical Design. The contributions of Prof. Rahman to the uplifting of science in Pakistan in his capacity as the Federal Minister for Science & Technology and later as Chairman Higher Education Commission were acknowledged by a high Civil Award of the government of Austria and TWAS prize for institution building as well as by four editorials in Nature. The Editorial board wishes health and prosperity to Prof. Atta-ur-Rahman in the years to come.

Inflammation is part of the body's response to internal and external environmental stimuli that normally eliminate the aggressor agent and restore the tissue physiology. However, when it becomes chronic, it can cause several pathologies such as cardiovascular, diabetes, rheumatoid arthritis, Alzheimer's autoimmune diseases and cancer. Currently, epidemiological data indicate that over 25% of all cancers are related to chronic infections and other types of unresolved inflammation. Further evidence of this relationship is the fact that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk to developing many types of cancers. Some randomized trials have shown that NSAIDs have protective action against colon adenomas, breast, prostate, and lung cancers. The inflammation present on tumor microenvironment is characterized by leukocyte infiltration, ranging in size, distribution and composition, as: tumor-associated macrophages (TAM), mast cells, dendritic cells, natural killer (NK) cells, neutrophils, eosinophils and lymphocytes. These cells produce a variety of cytotoxic mediators such as reactive oxygen and nitrogen species (ROS and RNS respectively), serine and cysteine proteases, membrane perforating agents, matrix metalloproteinase (MMP), tumor necrosis factor α (TNFα), interleukins (IL-1, IL-6, IL-8), interferons (IFNs) and enzymes, as cyclooxygenase-2 (COX-2), lipooxygenase-5 (LOX-5) and phospholipase A2 (PLA2), which activate or are activated by transcription factors as nuclear factor κB (NF-κB) and signal transducers and activators of transcription-3 (STAT3). Initially this paper will briefly review the main mediators present on tumor microenvironment, addressing the cytokines, chemokines, transcription factors, eicosanoid, and kinins and later, will present an overview of the role of inflammation in the different steps of carcinogenesis.

Autophagy, an intracellular process involved in removing and recycling cellular components, plays a major role in growth, development, and responses to stress and pathogens. Autophagy is compromised in many human diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). Autophagy malfunction is associated to an alteration of both innate and adaptative immune responses, defects in bacterial clearance, and malfunction of goblet and Paneth cells; all these perturbations are related to IBD and CRC pathogenesis. Preclinical data show that both inhibition and induction of autophagy have significant potential to be translated into the clinic. Inhibitors of TORC1 (rapamycin and rapalogs) have proven to be effective in IBD and in many models for CRCs; however, their clinical use has produced only modest success. Second generations of mTOR inhibitors, which target its kinase domain, have been more effective. Optimal antitumor efficacy is achieved by combination of agents with different molecular targets, such as proteasome or histone deacetylase inhibitors combined with autophagy inhibitors (hydroxychloroquine) or activators (everolimus). Clinical trials in course are assaying the effect of these compounds in combination with standard treatments of CRC. This review summarizes current knowledge about the autophagic machinery and its regulation, then it explores the relevance and impact of the malfunction of autophagy on the pathogenesis of IBD and CRC, and, finally, it discusses the therapeutic potential of molecules that regulate autophagy and their use for the treatment of these two diseases.

TGF-β1 is an anti-inflammatory cytokine recognised as a key regulator of immunological homeostasis and inflammatory responses. Furthermore, TGF-β1 is important for the regulation of cell growth, differentiation and apoptosis in a wide range of tissues including the intestinal epithelium. Reduced TGF-β1 activity is thought to be responsible for the development of autoimmune disorders in several pathological conditions, including inflammatory bowel disease [IBD]. Although the cause of IBD is not yet known, research has shown that a number of factors may be involved including environment, diet and genetics, as well as cytokine exposure. Importantly, IBD is also associated with an increased lifetime risk of developing colorectal cancer, which remains the fourth most common cancer worldwide, representing a significant therapeutic challenge. As functionally implicated in both maintenance of the immune response and tissue homeostasis in the colon, TGF-β1 signalling potentially sits at the crossroads between aberrant inflammation and colorectal tumorigenesis. Hence, the purpose of this paper is to review the evidence for cross talk between TGF-β1 signalling and pathways important for colorectal tissue homeostasis, with the emphasis on understanding how deregulation of TGF-β1 signalling contributes not only to aberrant inflammatory disease but also to colorectal tumour progression.

Reactive oxygen species (ROS) are well recognized for playing a dual role as both deleterious and beneficial species. ROS are products of normal cellular metabolism and under physiological conditions, participate in maintenance of cellular ‘redox homeostasis. Overproduction of ROS, results in oxidative stress. Oxidative stress is a deleterious process that leads to lung damage and consequently to various disease states. The lung is a highly specialized organ that facilitates uptake of oxygen and release of carbon dioxide. Persistent inhalation of the invading pathogens or toxic agents may result in overwhelming production of ROS. Oxidants initiate a number of pathologic processes, including inflammation of the airways, which may contribute to the pathogenesis and/or exacerbation of airways disease. During inflammation, enhanced ROS production may induce recurring DNA damage, inhibition of apoptosis, and activation of protooncogenes by initiating signal transduction pathways. Therefore, it is conceivable that chronic inflammation-induced production of ROS in the lung may predispose individuals to lung diseases. In this review, we discuss mechanisms of oxidant stress in the lung, the role of oxidants in lung disease pathogenesis and exacerbation.

Cigarette smoking is the most recognized risk factor for many inflammatory diseases such as cardiovascular diseases, chronic obstructive pulmonary disease and for a number of malignances such as lung cancer. Lung cancer is currently considered the leading cause of cancer-related deaths because its aggressive nature and the lack of effective therapeutic options. Recent advances in molecular biology and immunology have improved the knowledge on different mechanisms implicated in lung cell malignant transformation, progression and metastasis, thus presenting an exciting new era for lung anticancer therapies. The way by which cigarette smoke may induce lung malignancy includes a large number of different mechanisms and substances, most of them currently unknown. Thus, identified carcinogenic compounds of cigarette smoke may induce themselves a direct cytotoxicity and mutagenic action on lung epithelial cells by means of generation of somatic mutations, epigenetic events, epithelial cell to mesenchymal cell transformations, as well as by chronic cell damage. However, the fact that there is a relative high prevalence of ex-smoker who may develop lung cancer after years of smoking cessation suggest that other causes are also implicated. Thus cigarette smoke-induced chronic lung inflammatory microenvironment, oxidative stress and cell structural alterations such as the increase of cell proliferation, angiogenesis and apoptosis arrest are irreversible processes that have a high influence in lung tumor growth. In this review we focused in current knowledge on the mechanisms implicated in cigarette smoke-induced lung chronic inflammatory processes leading to lung carcinogenesis, as well as in current therapies based on novel molecular advances.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder caused by deregulated immune responses in a genetically predisposed individual. This is a complex process mediated by cytokines, chemokines, adhesion molecules, cytoplasm nuclear receptors, among others. Recent data support a participation of the endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in IBD. Moreover, now it is evident that chronic degenerative pathologies, including IBD, share comparable disease mechanisms at the cellular level with alteration of the autophagy mechanisms. Mounting evidence suggests that the risk of developing colorectal cancer (CRC) is dramatically increased in patients with chronic inflammatory disease. Chronic inflammation in IBD exposes these patients to a number of signals known to have tumorigenic effects including nuclear factor kappa B (NF-κB) activation, proinflammatory cytokines and prostaglandins release and reactive oxygen species (ROS) production. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing, or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon cancer chemopreventive properties of phytochemicals derived from both plants (curcumin, resveratrol, epigallocatechin gallate, quercetin or genistein) and substances from marine environment, including microalgae species and their products. This review summarizes the mechanisms by which these naturally occurring compounds may mediate chemopreventive effects on cancer. These actions include induction of cell cycle arrest and apoptosis, inhibition of cell proliferation, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.

Inflammation is an important contributor to the development and progression of all human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs), bind to specific receptors that activate signaling pathways driving to the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, including non-steroidal anti-inflammatory drugs (NSAIDs), are well documented agents that inhibit tumor growth and prevent tumor development specially due to long-term use. NSAIDs also alter gene expression independently of COX inhibition which also appear to contribute to the anti-tumorigenic activity of these drugs. In a dermatologic point of view, most investigations are oriented to improve the current knowledge related to the pathogenesis of malignant melanoma, a prevalent skin cancer characterized by a rapid progression with frequent metastases and a poor response to the different available treatments. In the present issue we review the role of inflammation in cutaneous malignant melanoma and its impact on cancer pathogenesis. This topic represents an exciting new area of research, and could potentially result in new targets for melanoma therapy in the future.

The development of new drugs that can be valuable for the evolution of diseases' treatment is a goal for different areas of research, namely natural products chemistry, molecular biology and biochemistry, pharmacology, medicinal chemistry, synthetic organic chemistry and analytical chemistry. Nature is the main source of compounds for pharmaceutical purposes, either by providing the natural organic chemical compounds of interest or as a source of inspiration for the design of new drugs. The known anti-inflammatory and anticancer agents belong to a great diversity of structural skeletons since inflammatory and cancer processes involve many different biological targets. Their origins extend to plants, fungi, bacteria, and marine organisms, besides those produced by semi-synthesis and total synthesis. The tasks of the organic chemist are the screening, the structure assignment, and the semi and total syntheses of active molecules. Herein the screening and assignment of new active structures is addressed, together with other aspects, namely the improvements, both in availability and in effectiveness of action that can be achieved from new derivatives by synthetic or semi-synthetic strategies. Some aspects of drug delivery of anti-inflammatory and anticancer agents are considered. The bibliography presented is far from being exhaustive due to the prodigious number of published works. Instead, the most significant contributions in the scope of this review are described. The active compounds are organised by their biosynthetic origins as terpenoids; macrolides, polyketides and ansamycins; phenolics; alkaloids; peptides; glycoconjugates; other compounds, and food compounds.

Background: There is evidence that aspirin is effective for the chemoprevention of colorectal cancer. Due to their similar pharmacodynamics, the use of other non-steroidal anti-inflammatory drugs (NSAIDs) has been suggested for other cancer sites. Although this possibility has been discussed in the literature, uncertainty remains about the actual effects of NSAIDs other than aspirin in nongastrointestinal cancer. Objective: To summarize the best available evidence of the primary chemopreventive effects of non-aspirin NSAIDs for nongastrointestinal cancer. Methods: Our inclusion criteria were narrative or systematic reviews, clinical guidelines and, if they had not been previously included, primary controlled studies that evaluated the effectiveness of non-aspirin NSAIDs in preventing non-gastrointestinal cancer in healthy individuals. Studies were retrieved from the following databases: Guidelines.gov, BMJ Clinical Evidence, TRIP database, UpToDate, MEDLINE, CANCERLIT, Embase, CINAHL, ISI Web of Science and Scopus. Two independent reviewers selected eligible studies. Data were extracted by one reviewer and crosschecked by two others. Results: We found 9,984 non-duplicated articles and included 56 eligible studies. Most of these studies were observational. The studies reported conflicting results or no statistically significant associations between the use of non-aspirin NSAIDs and risk of lung, ovary, bladder, prostate, skin, and head and neck cancers. In contrast, an increased risk of renal cell carcinoma and a reduced risk of breast cancer were found to be statistically significant. The included studies had methodological limitations, which reduces our confidence in their results. Conclusions: We did not find sufficient evidence to support the use of the non-aspirin NSAIDs for the primary chemoprevention of a wide variety of non-gastrointestinal cancers. This scenario suggests caution when considering the routine use of non-aspirin NSAIDs. Additional well-conducted controlled studies may provide more conclusive evidence on this issue, but there are concerns about the risks of such exposure.