Current Pharmaceutical Design - Volume 21, Issue 21, 2015

Vitamin D, beyond its classical roles in the regulation of calcium and phosphorus homeostasis and bone metabolism, has been implicated in multiple pathological processes, including progression from inflammation to cancer development and also involvement in autoimmune diseases as well as cardiovascular disorders. In this review, we shall discuss the different roles of vitamin D and its therapeutic targets in different gastrointestinal diseases, focusing on colorectal cancer (CRC) and inflammatory bowel disease (IBD). To this end, vitamin D deficiency has been identified as a risk factor of CRC. On the other hand the active metabolite of vitamin D, 1, 25- dihydroxyvitamin D3 (1, 25(OH)2D3) has multiple anti-cancerous benefits including inhibition of proliferation, induction of apoptosis, promotion of differentiation and suppression of angiogenesis in tumors. In IBD, vitamin D is involved in the pathogenic process through the normalization of immune responses in the colon. With these experimental findings, well-designed and large-scale clinical trials are warranted to further define the therapeutic action of vitamin D in the prevention and/or treatment of IBD and further on CRC in humans.

Gastrointestinal (GI) tract cancers account for a significant proportion of human malignancies. While classical multistep carcinogenesis is characterized by the stochastic accumulation of genetic mutations, additional extrinsic factors can also contribute to tumor promotion. Inflammation plays a critical role in cancers of the GI tract, for which the two major etiological factors are tissue injuries and altered microbiota. Together with infiltrating immune cells, all of these components generate a dynamic tumor microenvironment that inevitably induces malignant progression and metastatic growth. Crosstalk between tumor and immune cells is mediated by a multitude of pro- and anti- inflammatory cytokines. Their biological actions are propagated in both tumor and immune cells through an intricate network of intracellular signaling pathways that ultimately modulate essential cellular functions such as tumorigenic properties and lineage specification. Using the vast amount of information stored in the database on genetic changes associated with human cancers that has been collected over the past decades, this book chapter will first profile the genomic and transcriptomic landscapes of some of the major GI tract cancers. Critical driver genes and pro-inflammatory cytokines will be discussed in detail. The mechanisms by which genetic mutations in cancer cells can provoke inflammation and vice versa will be explored. The way in which the symbiotic relationship between cancer cells and chronic inflammation can modulate tumor cell behavior will be examined. We will present some of the most recent advancements in the targeting of inflammation for the treatment of GI tract cancers.

Gastrointestinal (G-I) cancers are one of the most common malignant tumors worldwide. Symptoms relate to the organ affected in the G-I tract are non-specific, making early detection and effective treatment difficult to achieve. Epithelial-mesenchymal transition (EMT), a reversible and dynamical process, can disperse cells in embryos, form mesenchymal cells in injured tissues, and regulate embryonic stem cell differentiation. A variety of signaling molecules and distinct pathways are involved in the initiation and progression of EMT. Recent evidence has established that EMT may endow G-I cancer cells with the capacity to invade surrounding tissues, resist apoptosis, migrate to distant organs, and develop chemoresistance. Targeting these signaling molecules and pathways associated with EMT may provide clinicians with a new approach to the treatment of G-I malignancy.

Peroxisome proliferator-activated receptorδ (PPARδ) belongs to the PPARs receptor family including PPARα, PPARδ, and PPARγ. PPARδ is a ligand-activated transcription factor that plays a critical role in regulating cancer progression. PPARδ-linked tumorigenesis was first identified in colorectal cancer, which is demonstrated by the following evidences, so PPARε is a potential drug target for colorectal cancer. In contrast, some observations show that PPARδ negatively regulates colorectal cancer event. In the present review, the recent progress of PPARδ signaling-mediated colorectal cancer is covered.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in males and the second in females worldwide. Accumulating evidence has demonstrated that patients with chronic inflammation in bowels have an increased risk to develop CRC. Various inflammatory cells and mediators produced during chronic inflammation are orchestrated through different molecular signaling pathways and lead to the formation of a microenvironment in favor of tumorigenesis. Vascular endothelial growth factor (VEGF), which can be induced by chronic inflammation, plays a pivotal role in tumor angiogenesis as well as tumor growth and metastasis. Antiangiogenic therapy targeting VEGF and its signaling pathways represents a promising strategy to inhibit colorectal tumorigenesis. Indeed, anti-angiogenic agents modulating VEGF ligands and their receptors have already exhibited great potential in treating patients with CRC, especially when combined with conventional chemotherapeutic agents. This review discusses the promoting role of chronic inflammation in colorectal tumorigenesis at different stages including tumor initiation, promotion, progression and metastasis, highlighting the contributory role of VEGF in angiogenesis during the development from chronic inflammation to CRC. It also describes the clinical significance of anti- VEGF therapy in the treatment of such disease.

Collectively, cancers of the gastrointestinal (GI) tract (including the esophagus, stomach, duodenum, colon, rectum, liver, gall bladder and bile ducts) are the most prevalent and deadly worldwide. A common denominator in the pathogenesis of these GI tract cancers is chronic inflammation, as evidenced by the fact that sufferers of inflammatory bowel disease (IBD) are significantly more susceptible to colon cancer than healthy individuals. However, since only a relatively small proportion of individuals with chronic inflammatory conditions such as IBD go on to develop cancer, research has focused on identifying discrepancies in the host immune system that may be responsible for promoting carcinogenesis in inflamed tissue. To this end, molecular pathways linking inflammation and cancer are emerging, with one series of candidates being members of the Toll-like receptor family.

Ibuprofen is a non-steroidal anti-inflammatory drug of generalized use with over-thecounter availability. Population-based studies have provided evidence that its long-term use is associated with a 30-60% decrease in the risk of developing major types of cancer. Initially, the underlying molecular mechanism was thought to be exclusively dependent on its inhibitory effect on cyclooxygenase activity, which is involved in the inflammatory response. However, numerous studies have now shown that the cancer chemopreventive properties of ibuprofen are much more complex and likely involve multiple COX-2-independent effects. Here we review the current knowledge on COX-independent effects of ibuprofen, which affect changes in gene expression or alternative splicing and act through various cell cycle- and apoptosis-regulating pathways, including β-catenin, NF-ΚB, PPARγ and p53.

Chronic inflammation increases the risk of developing cancer. For example, patients with severe and prolonged inflammatory bowel disease, particularly ulcerative colitis, have a significantly higher risk of developing colorectal cancer. Serine proteases coordinating the coagulation cascade and immune cell proteases play important roles in regulating the inflammatory response through their actions on protease-activated receptors (PAR). PARs and their activating proteases have also been implicated in many cancers, including CRC. Importantly, the actions of proteases could be important for mediating the transition from chronic inflammation to cancer. PAR activation has been shown to have pro-tumourigenic effects including the production of matrix metalloproteinases that can promote tumour cell growth and metastasis, and transactivation of the epidermal growth factor receptor, which is a main target for cancer treatment. Additionally, PAR activation can also result in increased expression of cyclooxygenase (COX)-2, an important enzyme mediating inflammation, resolution, and cancer progression. In this review, we will highlight our current knowledge about the effects of proteases and their receptors on intestinal inflammation and cancer, and explore the potential role of PAR-induced COX-2 on colitis-associated cancer.

Ulcers in the stomach, duodenum, ileum/jejunum and colon may look alike grossly and microscopically, but they have very different etiologies and pathogenesis. Unfortunately, there is virtually no etiologic treatment for any of these lesions which are also accompanied by limited or extensive inflammation. This article reviews four groups of new antiulcer drugs discovered and patented in our lab in Boston and Long Beach/Irvine (Table 1). Actually, the first group, pyrazole and its derivatives can be used for prevention, i.e., long lasting protection of gastric mucosa against alcohol- or NSAID-induced erosions. Dopamine seems to be a new etiologic treatment for both upper and lower GI tract ulcers. Angiogenic growth factors like bFGF or PDGF (daily administration as peptides orally or by rectal enemas, or as single or double-dose of gene therapy) accelerated the healing of gastroduodenal ulcers and UC, while VEGF seems to be effective only for upper GI tract ulcers. Last but not least, a novel group of angiogenic steroids which not only stimulate new blood vessel formation and granulation tissue production (essential elements of healing of ulcer types) but may also exert mild or prominent antiinflammatory action and seem to be ideal drugs for the treatment of IBD.

We herein reviewed the mechanism underlying the gastric hyperemic response following barrier disruption, with a focus on cyclooxygenase (COX) isozymes, prostaglandin (PG) E2, and capsaicin-sensitive afferent neurons. Mucosal damage was induced by exposing the stomach to 20 mM taurocholate (TC) with 50 mM HCl. The TC treatment disrupted surface epithelial cells, and then increased acid back-diffusion and mucosal blood flow (GMBF) in the stomachs of rats or wild-type mice. This hyperemic response in the rat stomach was inhibited by indomethacin without affecting acid back-diffusion, which resulted in the aggravation of lesions. The effect of indomethacin was mimicked by loxoprofen and the selective COX-1 inhibitor, SC-560, but not by the selective COX-2 inhibitor, celecoxib. The GMBF responses induced by TC were similarly observed in the stomachs of wildtype mice and EP3 receptor knockout mice, but not in mice lacking the EP1 receptor or pretreated with an EP1 antagonist. The increase in the GMBF response associated with acid back-diffusion after the TC treatment was also inhibited by the chemical ablation of capsaicin- sensitive afferent neurons, but not capsazepine, a TRPV1 antagonist. Thus, endogenous PGE2 produced by COX-1 plays a role in the gastric hyperemic response following barrier disruption of the stomach by interacting with capsaicin-sensitive afferent neurons, mainly through EP1 receptors, and facilitating the GMBF response to acid back-diffusion. These findings have also contributed to a deeper understanding of mucosal defensive mechanisms following barrier disruption and the development of new strategies for the treatment of gastrointestinal diseases.

Hydrogen sulfide has potent anti-inflammatory and cytoprotective properties. In the gastrointestinal tract, hydrogen sulfide contributes significantly to mucosal defence and responses to injury. This includes promotion of resolution of inflammation and healing. Inhibition of hydrogen sulfide synthesis increases the susceptibility of the gastrointestinal mucosa to injury and delays healing processes. The beneficial effects of hydrogen sulfide have been exploited in the design of novel anti-inflammatory drugs that cause negligible gastrointestinal damage. Nonsteroidal anti-inflammatory drugs are known to be effective, when used chronically, in reducing the incidence of several types of cancer. However, the toxicity of these drugs, particularly in the gastrointestinal tract, greatly limits this use. On the other hand, the gastrointestinal-safe, hydrogen sulfide-releasing anti-inflammatories show great promise for chemoprevention of cancers. This paper reviews the evidence supporting important anti-inflammatory and cytoprotective effects of hydrogen sulfide, particularly in the gastrointestinal tract. Also reviewed are the approaches taken to develop safer anti-inflammatory and cancer chemopreventive drugs by exploiting the beneficial effects of hydrogen sulfide.

Chronic inflammation plays important roles in the initiation and development of various cancers, particularly gastrointestinal cancer. Cancer is characterized by stepwise accumulation of genetic and epigenetic alterations of genes. As a high risk factor for cancer, chronic inflammatory response produces great amount of mediators, including cytokines, reactive oxygen and nitrogen species, proteinases, which can induce genetic and epigenetic changes of cancer-associated genes and pathways. Furthermore, inflammation also modulates the expression of miRNAs that not only regulate the expression of tumor-related proteins but also enhance the tumor-promoting inflammatory process. In the current review, we summarize the mechanisms by which inflammatory mediators and signaling regulate the biosynthesis of miRNAs, as well as the involvement of miRNAs in the feedback loops promoting inflammation-associated carcinogenesis.

Inflammation is a beneficial response that can remove pathogens, repair injured tissue and restore homeostasis to damaged tissues and organs. However, increasing evidence indicate that chronic inflammation plays a pivotal role in tumor development, as well as progression, metastasis, and resistance to chemotherapy. We will review the current knowledge regarding the contribution of inflammation to epithelial mesenchymal transition. We will also provide some perspectives on the relationship between ER-stress signals and metabolism, and the role of these processes in the development of inflammation.

It is necessary to use more effective and safer therapies to treat the increasing prevalence of metabolic diseases. The evidence from several studies indicates that FGF21 which acts as an endocrine hormone can induce beneficial influence to metabolism without apparent adverse effects. Thus, the pharmacologic and physiologic actions of FGF21 play a key role in controlling substrate utilization and energy balance. Recently, the developments in the understanding of FGF21 have contributed to make FGF21 a viable and promising therapeutic agent. This review discusses the functions of FGF21 in the high-fat-diet response, the relationship between exercise and the expression of FGF21, the interaction between FGF21 and some important hormone, the potential of FGF21 pharmacology in human and the methods to prolong the half-life of FGF21. These perspectives about FGF21’s therapeutic potential highlight the importance of this molecule which could be a novel and attractive drug for metabolism disorder.

Protein-protein interactions (PPIs) are becoming highly attractive targets for drug discovery. Motivated by the rapid accumulation of PPI data in public database and the success stories concerning the targeting of PPIs, a machine-learning method based on sequence and structure properties was developed to access the druggability of PPIs. Here, a comprehensive non-redundant set of 34 druggable and 122 less druggable PPIs were firstly presented from the perspective of pockets. When tested by outer 5-fold cross-validation, the most representative model in discriminating the druggable PPIs from the less-druggable ones yielded an average accuracy of 88.24% (sensitivity of 82.38% and specificity of 92.00%). Moreover, a promising result was also obtained for the independent test set. Compared to other methods, the method gives a comparative performance, which is most likely due to the construction of a training set that encompasses less druggable PPIs and also the information of active pockets that have evolved to bind a natural ligand.