Current Pharmaceutical Design - Volume 19, Issue 7, 2013

MicroRNAs are small non-coding RNAs that negatively regulate gene expression through binding on the 3' untranslated region (UTR) of genes. Although microRNAs constitute a small fraction of the human genome, multiple studies have indicated their involvement in the pathogenesis of different types of cancer. Hepatocellular carcinoma (liver) is one of the most aggressive types of cancer with very few therapeutic options. Several studies have revealed that microRNAs are deregulated during liver cancer development and affect central oncogenic and anti-apoptotic liver cancer signaling pathways. Furthermore, the expression levels of specific microRNAs have been identified to be correlated with clinicopathological parameters and treatment responses in liver cancer patients. Here, we review how different epidemiological and liver cancer risk factors, such as the hepatitis B and C viruses, deregulate microRNA-gene circuits in the liver, contributing to liver cancer development. Furthermore, we describe how the most frequently deregulated microRNAs identified in liver cancer patients control their down-stream signaling pathways in liver cancer cells. In addition, we provide examples of microRNAs or microRNA inhibitors that have been used as liver cancer therapeutics and describe novel delivery technologies that could be potentially used in order to optimize the delivery of microRNAs in the liver without having any toxicity or side effects in other major organs. Taken together, there is ample evidence suggesting the deregulation of microRNA-gene circuits in liver, promising that the development of microRNA-based therapeutics could be a clinically viable approach for liver cancer patients.

Hepatocellular carcinoma (HCC) is one of the few cancers with a worldwide increasing trend of incidence, representing the third largest cause of cancer-related death. The initiation and progression of HCC depend on progressive accumulation of genetic and epigenetic defects that alter an array of signaling cascades via deregulation of signal activators and inhibitors. MicroRNAs (miRNAs) are small RNA molecules that post-transcriptionally repress gene expression including those signal molecules and thus are critical for many cellular pathways. However, the balance of this fine-tuning function is broken by the abnormal expression of miRNAs in various cancers through genomic alterations or epigenetic mechanisms. This review summarizes the current knowledge of the role of epigenetic aberrations, including histone methylation and deacetylation as well as DNA hypermethylation and hypomethylation in the aberrant regulation of miRNAs leading to activation of signaling pathways such as Ras, STAT3 and AKT/mTOR in HCC. Conceivably, the therapeutic efficacy of current chromatin-modifying drugs might be related to their capacity to reactivate previously silenced tumor-suppressive miRNAs and cause down-regulation of target oncogenes. Better understanding of the epigenetics-miRNA regulatory cascades in the control of the functionally significant pathways will provide new opportunities for the development of more effective therapeutic modality for HCC.

microRNAs (miRNAs) comprise a recently discovered class of non-coding RNAs with regulatory functions in posttranscriptional gene expression control. Many miRNAs are located in genomic regions that are frequently deleted in cancer, or are subject to epigenetic and transcriptional deregulation in cancer cells. The miRNA transcriptome of cancer cells is very different from that of their normal cell counterparts. miRNAs can exhibit oncogenic or tumor suppressive or even both properties depending on the specific targets and cellular context. It is becoming increasingly clear that miRNAs not only serve as useful tumor biomarkers with implications for diagnosis, prognosis and the prediction of treatment responses, but may also be used for targeted cancer treatment and even as therapeutics. In this review, we provide an overview of recent advances in our understanding of the tumor suppressor miRNAs and oncomiRs involved in the pathogenesis of leukemias and lymphomas, and their target transcripts in cancer signaling networks. In particular, we focus on the role of miRNAs in chronic lymphocytic and acute lymphoblastic leukemia and in B-cell lymphomas. In the second part, we review the various alternative strategies of targeting miRNAs in cancer therapy. Methods of oncomiR antagonization by antagomiRs or locked nucleid acids are contrasted with strategies that harness the tumor suppressive properties of certain miRNAs for cancer treatment. Preclinical progress, also with regard to delivery strategies, possible side effects and other pharmacological aspects, is presented along with results from the first human trials assessing the safety and efficacy of miRNA-targeting therapeutics.

There are several microRNAs that have been consistently reported to be differentially expressed in esophageal squamous cell carcinoma vs. normal squamous tissue, with prognostic associations for miR-21 (invasion, positive nodes, decreased survival), miR-143 (disease recurrence, invasion depth), and miR-375 (inversely correlated with advanced stage, distant metastasis, poor overall survival, and disease-free survival). There is also evidence that miR-375 regulates gene expression associated with resistance to chemotherapy. Hence, microRNA expression assays have the potential to provide clinically relevant information about prognosis and potential response to chemotherapy in patients with esophageal squamous cell carcinoma. Results are inconsistent, however, for microRNAs across different studies for esophageal adenocarcinoma (EAC) vs. its precursor lesion Barrett's esophagus. These inconsistencies may partly result from pathological and/or molecular heterogeneity in both Barrett's esophagus and EAC, but may also result from differences in study designs or different choices of comparator tissues. Despite these inconsistencies, however, several mRNA/protein targets have been identified, the cancer related biology of some of these targets is well understood, and there are clinico-pathological associations for some of these mRNA targets. MicroRNAs also have potential for use in therapy for esophageal cancers. The development of new delivery methods, such as minicells and autologous microvesicles, and molecular modifications such as the addition of aromatic benzene pyridine analogs, have facilitated the exploration of the effects of therapeutic microRNAs in vivo. These approaches are producing encouraging results, with one technology in a phase I/IIa clinical trial.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The molecular mechanism of GIST formation is among the best characterized of all human tumors. Activating mutations of the c-Kit-kinase (KIT), a member of the receptor tyrosine kinase III family, are present in 80% of GISTs. Gain-of-function mutations of platelet-derived growth factor receptor A (PDGFRA), a member of the same kinase family, are present in 35% of GISTs that lack KIT mutations. These mutations induce the overexpression and autophosphorylation of KIT and PDGFRA, and result in the activation of downstream signaling pathways. Imatinib, a KIT receptor inhibitor, was developed to treat GIST patients by inactivating signaling pathways. However, some GISTs, especially cases with mutations in exon 13 and 17 of KIT, are resistant to imatinib treatment. Therefore, another approach is needed to develop drugs for GIST treatment. Data also support dysregulation of microRNAs in the progression of many types of cancers. Studies demonstrate that microRNAs directly regulate KIT expression levels in GISTs, and inhibit GIST cell proliferation. This review summarizes the characteristics of GISTs, their molecular and clinical implications, the role of microRNAs in GIST tumorigenesis, and their possible therapeutic potential.

While the phenotypic changes involved in the esophageal oncogenic “cascade” are now well established, the molecular profiling of this pathway remains unreliable. Our understanding of the molecular dysregulations underlying the development/progression of cancer has recently been expanded by the characterization of a new class of small, noncoding RNA gene products, the microRNAs (or miRNAs). These “endogenous silencers” target a large number of genes, functioning as tumor suppressors or tumor promoters, depending on the activity of the targeted genes. In esophageal cancer, miRNA dysregulation plays a significant part in the molecular oncogenic pathway, in cancer prognosis, and in patients' responsiveness to neo-adjuvant and adjuvant therapies. In addition to these valuable features, miRNAs have been proposed as innovative therapeutics per se and as plausible biological targets in new treatment strategies.

MiRNAs are small noncoding RNA molecules that are often aberrantly over- or underexpressed in tumors, including colorectal cancer (CRC). Due to their capacity to regulate and thus fine-tune the expression of multiple target genes relevant in tumorigenesis, tumor progression, angiogenesis, metastasis and sensitivity towards chemotherapy, they influence various pivotal cellular processes with prognostic and therapeutic relevance in CRC. This review provides a comprehensive overview of miRNAs with established functional relevance in colorectal cancer, their established target genes and the resulting cellular and pathological phenotype(s). Furthermore, approaches towards therapeutic miRNA-based intervention are discussed. Those include viral or non-viral approaches of miRNA replacement therapy in the case of tumor-suppressing miRNAs, and multiple strategies for the inhibition of oncogenic miRNAs. Beyond the analysis of the functional relevance of a given miRNA as target molecule or a miRNA-based drug, several studies in preclinical in vivo models are described that provide the basis for possible future therapeutic intervention in man.

MicroRNAs (miRNAs) are small non-coding RNAs exhibiting critical functions as post-transcriptional regulators. Due to the importance and extensive influence of miRNAs on genes, dysregulation of miRNAs has been associated with various types of cancer, with more prominent being colorectal carcinoma (CRC). Increasing evidence suggests that miRNAs mediate the initiation and development of CRC and also act as potential biomarkers for both diagnosis and prognosis. In this review, we summarize the recent advancement of miRNA research in CRC, in particular, the miRNAs which interact with critical pathways such as p53, NF-kappa B, beta-catenin pathways and also play a significant role in the regulation of EMT and maintenance of cancer stem cell.

MicroRNAs (miRNAs) are approximately 22-nucleotide noncoding RNAs that constitute silencers of target gene expression and have emerged as key regulatory molecules of mammalian cell functions. Aberrant miRNA expression promotes pathologic conditions including hepatocellular carcinoma (HCC) and a variety of precancerous liver diseases, especially chronic hepatitis B and C, and liver cirrhosis. miRNAs may contribute to HCC development by acting as oncogenes or tumor suppressors. Specific alterations of miRNA expression have also been related to clinical features of HCC, such as stage, differentiation, prognosis, and response to adjuvant therapy. miRNA signatures may help define molecular profiles of liver diseases as biomarkers, and allow classification of different stages of cirrhosis and HCC progression. Either miRNAs, or anti-miRNA oligonucleotides (antagomirs) could be used for in vivo modulation of miRNA actions, and thus have significant potential in molecularly targeted therapy.

Gastric carcinogenesis is a complex multistep process involving genetic dysregulation of proto-oncogenes and tumorsuppressor genes, and has recently entered the era of microRNAs (miRNAs), a class of small non-coding RNAs that posttranscriptionally regulate gene expression and control various cellular functions. MicroRNAs are small (approximately 22 nucleotides) non-coding RNAs that play fundamental roles in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis. MicroRNAs have been revealed to be involved in various stages of cancer development, showing that abnormal miRNA expressions play critical roles in modulating expression of known oncogenes or tumor suppressor genes during cancer progression. Therefore, microRNAs can perform the function of onco-miRs or tumor-suppressor-miRs in gastric carcinogenesis. This review summarizes a current understanding of the connection between miRNAs and gastric cancer. Additionally, this paper outlines the applications of miRNAs in clinical practice, such as diagnosis, prognosis, detection, and therapy of gastric cancer.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally modulate gene expression by degrading or repressing the translation of target messenger RNAs (mRNA). Aberrant miRNA expression has been reported in OSCC, and this altered expression may be useful for the early detection of oral cancer. In this review we highlight the miRNAs profile of OSCC, the possible mechanisms underlying their altered expression together with their function in oral cancer development and progression. The modulation of miRNAs makes these small molecules potential markers for early oral cancer diagnosis and prognostic prediction as well as potential molecular tools for its treatment. Translational studies focusing on miRNAs could lead to the development of new tools for the management of patients with OSCC.

Esophageal cancer (EC) is a deadly disease. EC usually occurs as either adenocarcinoma (EAC) or squamous cell carcinomas (ESCC). The development of EAC generally follows the metaplasia-dysplasia-carcinoma sequence. Barrett's esophagus (BE) is a metasplastic precursor of EAC. Multiple global miRNA expression profiling and candidate gene studies have been performed in EAC and ESCC that clearly support the important roles of miRNAs in the pathogenesis of EAC and ESCC. A number of consistently dysregulated miRNAs have been identified in EAC and/or ESCC, including upregulation of miR-21, miR-192, miR-194, miR-106-25 polycistron (miR-25, miR-93, and miR-106b), miR-10b, miR-151, and miR-93, and downregulation of miR-375, miR-203, miR-205, miR-145, miR- 27b, miR-100, miR-125b, let-7c, etc. Most of these miRNAs are also dysregulated in other cancer types and their target genes have been extensively studied in different cancers. The prognostic value of miR-21 and miR-375 has been replicated in independent studies. Circulating miRNAs as potential biomarkers for early detection, prognosis, and treatment response have only been scarcely studied in EC. The association of genetic variations in miRNA regulatory pathway with EC risk or outcome is a largely uncharted territory. Future studies should be focused on the role of miRNAs in the prognosis of EC, the identification of circulating miRNAs and miRNA-related genetic variations as biomarkers in EC, and the biological mechanisms underlying the contribution of miRNA dysreguation to EC. A better understanding of roles of miRNA in EC developemnt may provide new avenues for the early detection, diagnosis, prognosis, and therapy of this deadly disease.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. They have been found to be dysregulated in many pathological conditions including cancer and play an important role during the progression of such disease. Recent efforts have been directed in translating the primary findings of miRNAs into clinical uses. This article gives a general overview on the potential of miRNAs as diagnostic and prognostic markers and also as therapeutic targets for gastrointestinal and liver cancers in animals and humans. Other contributors in this special series would focus in discussing the roles of specific miRNAs and their pathogenic mechanisms and therapeutic applications in different types of cancer in the gastrointestinal tract and liver.

Primary negative symptoms (affective flattening or blunting, alogia, avolition) are prominent in approximately 20% of individuals suffering from schizophrenia. These symptoms are particularly associated with impaired functional outcome and poor prognosis. This is in part due to the lack of specific and effective treatments despite the development and use of the second generation antipsychotics. There is increasing evidence that suggests that combined dysfunction of the dopamine and glutamate neurotransmitter systems may underlie some of the key clinical and pathophysiological features of schizophrenia. Specifically, hypofunction of the N-methyl-Daspartate receptor (NMDAR) at critical circuits within the brain appears to be an important mechanism. Thus, it would be anticipated that modulation of NMDAR function by increasing the availability of the glutamate co-agonist, glycine, within the synaptic cleft may provide a new therapeutic strategy for the management of schizophrenia. However, the direct glycine receptor agonists such as glycine and D-cycloserine (d-4-amino-3-isoxazolidinone) have demonstrated limited efficacy in studies to date. One of the most promising approaches for enhancing NMDAR function involves modification of the activity of the high affinity glycine transporter 1 (GlyT1). Numerous compounds have been synthesized, with the early compounds being substituted glycine derivatives such as sarcosine (N-methylglycine) and Org 24598. More recent developments have focused on the non-amino acid derivatives Org 25935 (cis-N-methyl-N-(6-methoxy-1- phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)amino-methylcarboxylic acid hydrochloride) and bitopertin (RG 1678). Of the molecules being investigated currently, a proof-of-concept, double-blind study of bitopertin has yielded encouraging findings, with a significant decrease in negative symptoms and no major tolerability or toxicity issues. Further studies are needed to confirm these findings and to explore the potential application of these therapies in different clinical situations in order to achieve greatest effect on negative symptoms. In addition, there is still much to be learned about this class of agents in terms of other potential domains of efficacy such as positive symptoms or cognition as well as long-term safety.

The aim of this study was to investigate whether topical application of fibrin-binding oligopeptides derived from FN promotes wound healing in streptozotocin (STZ)-induced diabetic rats. Oligopeptides including fibrin-binding sequences (FF3: CFDKYTGNTYRV, FF5 : CTSRNRCNDQ) of FN repeats were synthesized. Each peptide was loaded in 15 x 15 mm fibrous alginate dressings, and the release kinetics of the peptides was evaluated using trinitrobenzene sulfonic acid for 336 hours. Two full-thickness cutaneous wounds were prepared on the dorsal skin of each 75 diabetes induced rats. Each wound was divided into FF3-loaded alginate dressing group, FF5-loaded alginate dressing group, alginate dressing group and negative control group. Animals were sacrificed at day 0,3,7 and 14. The wound closure rate, inflammation degree, expression of TGF-β1 and hydroxyproline contents were evaluated. Both FF3 and FF5 peptides were released rapidly within the first 24 hours. FF3-loaded dressing treated wounds closed significantly faster than other wounds at day 3. And at day 14, FF3- & FF5- loaded dressing treated wounds demonstrated less inflammatory cells infiltration than alginate dressing treated and negative group wounds. TGF-β1 positive cells were more abundant in FF3-, FF5-treated alginate dressing treated wound at day 3 and 14. At last, the hyrdroxyproline contents in the FF3, FF5 group were higher at day 7 and day 14. Topical application of fibrin-binding domain synthetic oligopeptides from FN resulted in acceleration of full-thickness cutaneous wound healing in diabetic rats.

Gut immune system is daily exposed to a plethora of antigens contained in the environment as well as in food. Both secondary lymphoid tissue, such as Peyer's patches, and lymphoid follicles (tertiary lymphoid tissue) are able to respond to antigenic stimuli releasing cytokines or producing antibodies (secretory IgA). Intestinal epithelial cells are in close cooperation with intraepithelial lymphocytes and possess Toll-like receptors on their surface and Nod-like receptors (NLRs) which sense pathogens or pathogen-associated molecular patterns. Intestinal microbiota, mainly composed of Bacteroidetes and Firmicutes, generates tolerogenic response acting on gut dendritic cells and inhibiting the T helper (h)-17 cell anti-inflammatory pathway. This is the case of Bacteroides fragilis which leads to the production of interleukin-10, an anti-inflammatory cytokine, from both T regulatory cells and lamina propria macrophages. Conversely, segmented filamentous bacteria rather induce Th17 cells, thus promoting intestinal inflammation. Intestinal microbiota and its toxic components have been shown to act on both Nod1 and Nod2 receptors and their defective signaling accounts for the development of inflammatory bowel disease (IBD). In IBD a loss of normal tolerance to intestinal microbiota seems to be the main trigger of mucosal damage. In addition, intestinal microbiota thanks to its regulatory function of gut immune response can prevent or retard neoplastic growth. In fact, chronic exposure to environmental microorganisms seems to be associated with low frequency of cancer risk. Major nutraceuticals or functional foods employed in the modulation of intestinal microbiota are represented by prebiotics, probiotics, polyunsaturated fatty acids, amino acids and polyphenols. The cellular and molecular effects performed by these natural products in terms of modulation of the intestinal microbiota and mostly attenuation of the inflammatory pathway are described.

The treatment of tuberculosis and other mycobacterioses is still a major world health problem and new antimycobacterial compounds unrelated to approved drugs are in demand. Quaternary ammonium salts have revealed many usable properties especially as antimicrobials; they are widely used as disinfection and antiseptic agents. Some of these compounds, including pyridinium salts, have revealed substantial antimycobacterial action, although the presence of the cationic nitrogen itself is not sufficient for activity. A long Nalkyl chain is also not necessary for antimycobacterial activity, although it is associated with improved activity. Compounds that have shown significant in vitro activity, e.g., cetylpyridinium, N-(substituted alkyl)pyridinium salts, 3-[(5- cyclopentylpentyl)(substituted phenyl)amino]-1-methylpyridinium iodides or pyridinium alkyl ethers of steroids (good activity with minimum inhibitory concentrations – MIC from 0.4 μg/mL). However, most pyridinium salts have mild or moderate activity against fastand/ or slow-growing mycobacteria, including N-methylated isoniazids or pyridinium-based oximes. Moreover, a pyridinium ring is present in some cefalosporines (e.g., cefaloridine, ceftazidime and cefsulodine) with antimycobacterial properties. The N-oxidation of pyridine mostly resulted in retained or increased minimum inhibitory concentrations. Additionally, the action of pyridinium N-oxides against mycobacteria is not especially robust. The mechanism of action of pyridinium compounds remains elusive, but the inhibition of some mycobacterial enzymes has been described for a few derivatives.