Chemoprevention of Cigarette Smoke-Induced Alterations of MicroRNA Expression in Rat Lungs
ABSTRACT We previously showed that exposure to environmental cigarette smoke (ECS) for 28 days causes extensive downregulation of microRNA expression in the lungs of rats, resulting in the overexpression of multiple genes and proteins. In the present study, we evaluated by microarray the expression of 484 microRNAs in the lungs of either ECS-free or ECS-exposed rats treated with the orally administered chemopreventive agents N-acetylcysteine, oltipraz, indole-3-carbinol, 5,6-benzoflavone, and phenethyl isothiocyanate (as single agents or in combinations). This is the first study of microRNA modulation by chemopreventive agents in nonmalignant tissues. Scatterplot, hierarchical cluster, and principal component analyses of microarray and quantitative PCR data showed that none of the above chemopreventive regimens appreciably affected the baseline microRNA expression, indicating potential safety. On the other hand, all of them attenuated ECS-induced alterations but to a variable extent and with different patterns, indicating potential preventive efficacy. The main ECS-altered functions that were modulated by chemopreventive agents included cell proliferation, apoptosis, differentiation, Ras activation, P53 functions, NF-kappaB pathway, transforming growth factor-related stress response, and angiogenesis. Some microRNAs known to be polymorphic in humans were downregulated by ECS and were protected by chemopreventive agents. This study provides proof-of-concept and validation of technology that we are further refining to screen and prioritize potential agents for continued development and to help elucidate their biological effects and mechanisms. Therefore, microRNA analysis may provide a new tool for predicting at early carcinogenesis stages both the potential safety and efficacy of cancer chemopreventive agents.
SourceAvailable from: Ximena Paredes-Gonzalez[Show abstract] [Hide abstract]
ABSTRACT: Glucosinolates are a group of sulfur-containing glycosides found in many plant species, including cruciferous vegetables such as broccoli, cabbage, Brussels sprouts, and cauliflower. Accumulating evidence increasingly supports the beneficial effects of dietary glucosinolates on overall health, including as potential anticancer agents, because of their role in the prevention of the initiation of carcinogenesis via the induction of cellular defense detoxifying/antioxidant enzymes and their epigenetic mechanisms, including modification of the CpG methylation of cancer-related genes, histone modification regulation and changes in the expression of microRNAs (miRNAs). In this context, the defense mechanism mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against oxidative stress and reactive metabolites of carcinogens. In this review, we summarize the cancer chemopreventive role of naturally occurring glucosinolate derivatives as inhibitors of carcinogenesis,with particular emphasis on specific molecular targets and epigenetic alterations in in vitro and in vivo human cancer animal models.06/2015; 1(3). DOI:10.1007/s40495-015-0017-y
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ABSTRACT: Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles as a carrier. This study evaluated the ability of lipid nanoparticles to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate, and resveratrol. The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate [CSC] and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. Nanoparticles decreased the toxicity of resveratrol and increased its ability to counteract CSC cytotoxicity. Nanoparticles significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. By contrast, this potentiating effect was observed at all tested doses of resveratrol, nanoparticles dramatically increasing resveratrol induced apoptosis in CSC-treated cells. These results provide evidence that nanoparticles are highly effective at increasing the efficacy of lipophilic drugs (resveratrol) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid nanoparticle delivery.Carcinogenesis 02/2015; DOI:10.1093/carcin/bgv008 · 5.27 Impact Factor
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ABSTRACT: miRNAs are endogenous small non-coding RNAs of 20–22 nucleotides that repress gene expression at the posttranscriptional level. There is growing interest in the role of miRNAs in cancer chemoprevention, and several naturally occurring chemopreventive agents have been found to be modulators of miRNA expression both in vitro and in vivo. Moreover, these chemopreventive phytochemicals commonly possess anti-oxidative and/or anti-inflammatory properties, and Nrf2 has been extensively studied as a molecular target in cancer prevention. The crosstalk between miRNAs and the traditional cellular signaling pathways of chemoprevention remain to be fully elucidated. This review summarizes the data regarding the potential interactions between miRNAs and anti-oxidative and anti-inflammatory pathways. Cellular redox homeostasis can affect the biogenesis and processing of miRNAs, which in turn regulate the Nrf2 pathway of detoxifying/anti-oxidative genes. We also discuss the miRNA regulatory mechanisms in relation to inflammation-related cancer signaling pathways.01/2015; 1(1). DOI:10.1007/s40495-014-0013-7