Exploiting the therapeutic potential of microRNAs in human cancer

Dysregulation of microRNAs (miRNAs) has been widely shown to be associated with the development and progression of cancer. Recent studies discovered a handful of miRNAs with great potential to act as therapeutic targets in various human cancers. Inhibition or overexpression of these oncomirs may regulate the expressions of their associated genes, which in turn represses the proliferation or metastasis of different cancers. Some miRNAs can reverse the phenotype of epithelial–mesenchymal transition, while others can be utilized to sensitize cells to DNA-damaging drugs. Most of their anticancer abilities have been validated in preclinical animal models. A merit of miRNA-based therapy is that it can target plenty of genes in different signaling pathways, but this also comes with the drawback of many unknown off-target effects. In addition, successful delivery is also a major obstacle to effective miRNA-based therapeutics. Nevertheless, new findings from recent studies and the rapid advances in systemic drug delivery systems provide an optimistic perspective on the evolution of the field.     

Exploiting the therapeutic potential of microRNAs in human cancer

Dysregulation of microRNAs (miRNAs) has been widely shown to be associated with the development and progression of cancer. Recent studies discovered a handful of miRNAs with great potential to act as therapeutic targets in various human cancers. Inhibition or overexpression of these oncomirs may regulate the expressions of their associated genes, which in turn represses the proliferation or metastasis of different cancers. Some miRNAs can reverse the phenotype of epithelial-mesenchymal transition, while others can be utilized to sensitize cells to DNA-damaging drugs. Most of their anticancer abilities have been validated in preclinical animal models. A merit of miRNA-based therapy is that it can target plenty of genes in different signaling pathways, but this also comes with the drawback of many unknown off-target effects. In addition, successful delivery is also a major obstacle to effective miRNA-based therapeutics. Nevertheless, new findings from recent studies and the rapid advances in systemic drug delivery systems provide an optimistic perspective on the evolution of the field.     

Wnt signaling as potential therapeutic target in lung cancer

Introduction: Wingless-type (Wnt) signaling is tightly regulated at multiple cellular levels and is dysregulated in lung cancer. Therefore, it offers therapeutic targets for developing novel agents for lung cancer treatment.

Areas covered: In this article, we discuss the role of the Wnt signaling pathway in lung cancer, highlighting the aberrant activation of Wnt in lung cancer stem cells and its implication in resistance to radiotherapy, chemotherapy and targeted therapy. We also expound the regulatory roles of microRNAs in Wnt signaling, as well as the potential of the Wnt pathway to provide biomarkers and therapeutic targets in lung cancer. The potential use of small molecule and biological inhibitors targeting the Wnt pathway for lung cancer therapy and prevention is also discussed.

Expert opinion: Wnt signaling plays an important role in the development and metastasis of lung cancer; the pathway provides targets to develop agents towards for cancer prevention and therapy. A number of clinical trials have shown the effectiveness of Wnt pathway inhibitors in epithelial tumors. However, the side effects should be considered. Nevertheless, the results from clinical studies suggest that inhibitors targeting the Wnt signaling show promise against lung cancer.     

The therapeutic mechanisms of ranpirnase-induced enhancement of radiation response on A549 human lung cancer

AIM: The goal of this study was to investigate the therapeutic potential of combining radiation therapy and cytotoxic RNase, ranpirnase (ONCONASE; ONC), in human lung tumor models in vitro and in vivo. As translational implications, the non-invasive monitoring response to individual therapy with ONC was also investigated to determine the underlying therapeutic mechanisms. MATERIALS AND METHODS: A clonogenic survival assay was used to measure the effect of ONC and radiation on A549 human non-small cell lung carcinoma (NSCLC) cells. H&E staining, TUNEL staining and caspase-3-antibody labeling were used for in vivo analysis of apoptosis. A growth-delay assay was applied to detect the therapeutic potential of ONC as a radiation sensitizer in vivo. ONC-induced changes in blood flow and biochemical metabolites were measured by various noninvasive dynamic contrast enhanced magnetic resonance imaging (DCE MRI), non-localized 1H magnetic resonance spectroscopy (MRS), and near-infrared spectroscopy (NIRS) methods. RESULTS: ONC at 5-10 microg/ml sensitized the radiation response of A549 tumor cells in vitro. Remarkable increases in ONC-induced apoptosis in vivo were observed in caspase-3 antibody labeling and TUNEL staining assays. ONC significantly increased the radiation-induced tumor growth delay of A549 tumors. It was observed, when using a DCE MRI method, that there were significant increases in K(trans) values at the rim of tumor regions at 1.5 h post-injection of ONC. When using non-localized 1H MRS, an approximately 20% decrease in lactate levels with ONC was found. CONCLUSION: ONC may be a new and promising drug in the treatment of NSCLC as a radiation therapy enhancer.     

Gene transfer to the lung: Lessons learned from more than 2 decades of CF gene therapy

Gene therapy is currently being developed for a wide range of acute and chronic lung diseases. The target cells, and to a degree the extra and intra-cellular barriers, are disease-specific and over the past decade the gene therapy community has recognized that no one vector is good for all applications, but that the gene transfer agent (GTA) has to be carefully matched to the specific disease target. Gene therapy is particularly attractive for diseases that currently do not have satisfactory treatment options and probably easier for monogenic disorders than for complex diseases. Cystic fibrosis (CF) fulfils these criteria and is, therefore, a good candidate for gene therapy-based treatment. This review will focus on CF as an example for lung gene therapy, but lessons learned may be applicable to other target diseases.     

Human immune response to recombinant human proteins

Delivery of pharmacological doses of proteins to people has raised concerns of inducing immune responses, especially when the protein is provided in multiple doses over an extended period of time. Immune responses could impact the therapeutic exposure and efficacy of the protein itself. In addition, there have been fears of anaphylaxis or autoimmunity. This review summarizes the available literature regarding the measurement and evaluation of immune responses observed during clinical assessment of recombinant human proteins. Immune responses have ranged from none at all to inactivation and/or accelerated clearance. Presence of antibodies does not necessarily impact therapeutic viability. While responses are related to frequency and route of delivery, there is no clear relationship that enables one to predict the clinical experience.     

Reprogramming the oncogenic response: SET protein as a potential therapeutic target in cancer

Introduction: SET is a multitask oncoprotein that promotes the initiation and progression of cancer. Overexpression of SET has been characterized as being tumor-specific and is associated with adverse clinical outcomes in many different human malignant diseases. Notably, SET has been shown to promote the development of therapeutic resistance in cancer cells.

Area covered: In this review, we summarized the currently available evidence relating to the oncogenic roles, biological functions and clinical relevance of SET protein in cancer. The anti-cancer effects of three different SET antagonists undergoing preclinical investigation are also discussed.

Expert opinion: Emerging evidence supports the critical role of SET in regulating various different cancer hallmarks. Targeting the SET-associated protein interfaces may be a potential anti-cancer strategy for future development. However, more studies are required to clarify the best strategy to combine SET antagonists with other anti-cancer treatments and to explore possible biomarkers that predict responsiveness.     

Lessons learned from taking data collection to the "hood"

Culturally appropriate measures are needed to analyze the effectiveness of HIV prevention interventions. An effective strategy to ensure the culturally appropriateness of measures is the inclusion of participants from the targeted community via participatory action research. Conducting the research process within the community is one method of maximizing greater community participation. The purpose of this paper is to describe a method of pilot testing an instrument within community settings. Findings presented focus primarily on the process of the method, rather than on a statistical outcome testing of the instrument. The sample was 200 African-American women recruited in networks drawn from two rural and two mid-sized counties in North Florida. Methodological issues encountered and resolved through ongoing process evaluation are presented as lessons learned with recommendations and implications.     

PASS-assisted exploration of new therapeutic potential of natural products

The use of drug substances derived from plants, fungi, bacteria, and marine organisms are “Mother Nature Gift” for diseases of mankind. Many of these are discovered serendipitously and have a long tradition in medicine. Till date, the use of natural products, their semisynthetic and synthetic derivatives have been mostly confined to their ethnic use. But it has been well known that each substance has a wide spectrum of biological activities as evident from some new uses of many old drugs. PASS (Prediction of Activity Spectra for Substances) has been employed as a strong potential tool to predict the biological activity spectrum of synthetic substances for the discovery of new drugs. But the potential of PASS to predict the biological activity spectra of natural products is still underestimated. The present study was therefore undertaken to investigate and correlate the biological activity spectrum of the main phytoconstituent of some selected Indian medicinal plants with their reported biological activities in order to evaluate the applicability of PASS. Further, the unexplored but PASS-predicted activities having good activity score (Pa > 0.7) for particular structure were listed as hidden potential of the plant.     

Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer

Sphingosine-1-phosphate (S1P) is an important regulator of cancer development and progression. Its cellular concentration is controlled predominantly by sphingosine kinase (SK) and sphingosine-1-phosphate lyase (SPL). In the current study we showed that mRNA expressions for both SK and SPL were up-regulated throughout all four disease stages in human breast cancer patients. Exogenous administration of S1P produced a bell-shaped dose response for apoptosis in normal mammary gland MCF12A cells but a sigmoid-shaped apoptotic response in breast cancer MCF7 cells. Co-administration of S1P enhanced the cytotoxicity of anticancer drug docetaxel against MCF7 cells.     

Mechanisms used by human papillomaviruses to escape the host immune response

The greatest risk factor for the development of cervical and other cancers that have been linked to the human papillomavirus (HPV) family is the persistence of the virus. To persist for the decades required to develop HPV-related cancers, the virus must escape host immunity. HPV is a simple DNA virus that has evolved to escape immune attack by a combination of stealth and interference. This review focuses on the mechanisms by which HPV can evade recognition by the host immune system.     

参附注射液对肺癌患者围手术期免疫功能的调节作用

目的研究肺癌患者围手术期免疫功能情况及参附注射液的调节作用。方法 32例肺癌患者根据病理学结果随机分为治疗组和对照组 ,治疗组患者从手术前 3天到术后 14天 ,每天静脉滴注参附注射液 5 0ml,手术过程中静脉滴注 5 0ml;对照组除不用参附注射液外 ,其它条件与治疗组相同。于术前、术毕、术后 3天、术后 14天抽取静脉血监测补体C3 、C4,免疫球蛋白IgG、IgA、IgM ,C反应蛋白 (CRR)和血常规。结果术后 3天、7天 ,治疗组患者血浆补体C3 、C4和C反应蛋白、白细胞总数明显低于对照组 (P <0 .0 5 ) ;而免疫球蛋白IgG、IgA、IgM则明显高于对照组 (P <0 0 5 ) ;中性粒细胞分类 (N % )两组无显著性差异 (P >0 0 5 )。结论参附注射液对肺癌患者围手术期免疫功能有较好的调节作用。     

Lessons learned from the clinical development of oral peptides

The oral delivery of peptides and proteins has been hampered by an array of obstacles. However, several promising novel oral delivery systems have been developed. This paper reviews the most advanced oral formulation technologies, and highlights key lessons and implications from studies undertaken to date with these oral formulations. Special interest is given to oral salmon calcitonin (CT), glucagon-like peptide-1 (GLP-1), insulin, PYY-(3-36), recombinant human parathyroid hormone (rhPTH(1-31)-NH₂) and PTH(1-34), by different technologies. The issues addressed include (i) interaction with water, (ii) interaction with food, (iii) diurnal variation, (iv) inter- and intra-subject variability, (v) correlation between efficacy and exposure and (vi) key deliverables of different technologies. These key lessons may aid research in the development of other oral formulations.     

Cutaneous response to intradermal histamine in lung cancer.

Recent evidence has suggested that human neoplastic patients show decreased blood histamine levels and cutaneous responses to intradermal histamine. In this study we evaluate the skin response to intradermal injections of histamine and IgE levels in 34 male patients with lung cancer (of which 21 had metastasis) and in 16 control subjects. Analysis of our data does not reveal any difference in the areas of wheal and flare between control subjects and lung cancer patients with or without metastasis. Moreover the evaluation of the different histologic cell type of lung cancer provides the same results. In addition, the sensitivity (Histamine Threshold Concentration) and reactivity (slopes) to histamine is not statistically different. No difference is found for IgE levels between controls and cancer patients. In the light of our finding we believe that in lung cancer patients skin response to intradermal histamine is not decreased, and therefore that the hypothesis concerning the existence of H1-histamine receptor antagonist released by tumour is not confirmed.     

Regulating the immune response to tumours

Naturally occurring regulatory T cells (Tregs) have been shown to suppress immune responses to self-antigens, thereby limiting autoimmunity. In the case of tumours, where immune responses to self-antigens are beneficial and lead to elimination of the tumour, such suppressive activity is actually detrimental to the host. Manipulation of Tregs holds great promise for the immunotherapy of cancer. Several studies performed using rodent models and indicate that Tregs cells inhibit effective anti-tumour immune responses and that their removal promotes tumour rejection. The increasing number of studies of Tregs in patients with cancer also point to a role for these cells in promoting disease progression. This review summarises the findings of these studies and addresses the advantages and potential pitfalls of manipulating Treg activity for the treatment of cancer.