Phytochemicals and Cancer Chemoprevention: Epigenetic Friends or Foe?

Cancer, as one of the non-communicable diseases, remains one of the leading causes of death around the world. Since immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and therapy sensitivity. Recent successes of therapeutic interventions in cancer and inflammatory diseases using epigenetic modifiers such as histone deacetylase inhibitors and inhibitors of DNA methylation suggest that epigenetic reprogramming plays an important role in the aetiology of these diseases. Epigenetic changes in DNA methylation patterns at CpG sites (epimutations) or corrupt chromatin states of tumor promoting genes and noncoding RNAs, recently emerged as major governing factors in tumor progression and cancer drug sensitivity. Epigenetic defects (epimutations) are thought to be more easily reversible (when compared with genetic defects) and, as such, have inspired efforts to identify novel compounds that correct epimutations or prevent disease progression. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for chemoprevention strategies. Numerous clinical, epidemiological and laboratory studies have identified various promising nutritional anti-inflammatory compounds as chemopreventive agents, which affect carcinogenic epigenetic marks in the body and the host immune system, and protect against aggressive cancer malignancies. This has recently launched reexploration of chemopreventive phytochemicals for identification of epigenetic targets which allow epigenetic (re)programming of cancer stem cells, prevent metastasis or sensitize for drug sensitivity. This review will discuss mechanisms of epigenome plasticity by cancer-inflammation and chemopreventive phytochemicals

DNA methylation of candidate genes in peripheral blood from patients with type 2 diabetes or the metabolic syndrome

Introduction: The prevalence of type 2 diabetes (T2D) and the metabolic syndrome (MetS) is increasing and several studies suggested an involvement of DNA methylation in the development of these metabolic diseases. This study was designed to investigate if differential DNA methylation in blood can function as a biomarker for T2D and/or MetS. Methods: Pyrosequencing analyses were performed for the candidate genes KCNJ11, PPARγ, PDK4, KCNQ1, SCD1, PDX1, FTO and PEG3 in peripheral blood leukocytes (PBLs) from 25 patients diagnosed with only T2D, 9 patients diagnosed with T2D and MetS and 11 control subjects without any metabolic disorders. Results: No significant differences in gene-specific methylation between patients and controls were observed, although a trend towards significance was observed for PEG3. Differential methylation was observed between the groups in 4 out of the 42 single CpG loci located in the promoters regions of the genes FTO, KCNJ11, PPARγ and PDK4. A trend towards a positive correlation was observed for PEG3 methylation with HDL cholesterol levels. Discussion Altered levels of DNA methylation in PBLs of specific loci might serve as a biomarker for T2D or MetS, although further investigation is required

Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Strategie i taktyki, stosowane w trakcie rozmów negocjacyjnych

Celem artykułu jest zaprezentowanie strategii i taktyk negocjacyjnych, sprzężonych z profilem negocjatora oraz uwarunkowaniami negocjacyjnymi. W ramach pojedynczej taktyki negocjacyjnej można realizować wiele technik. Negocjator, mając na uwadze etap rozmów, może wykorzystać właściwą technikę/techniki czy też taktykę/taktyki, których celem jest możliwie jak najdalej idące osiągnięcie założonego rezultatu negocjacyjnego, zgodnego z oczekiwaniami organizacji. W literaturze przedmiotu dostępne są informacje z zakresu stosowanych technik i taktyk negocjacyjnych, nie mniej jednak opisane są one najczęściej w odniesieniu do pojedynczego przypadku. W niniejszej pracy opisano i porównano poszczególne rodzaje technik i strategii negocjacyjnych, z jednoczesnym wskazaniem obszarów i sytuacji, w których mogą być wykorzystane na różnych etapach procesu negocjacyjnego.The main aim of this article is presenting strategies and negotiations tactics, tasks relate to them accordingly. Strategies and tactics are coupled with profile of negotiator and negotiating circumstances. As part of a single negotiation tactics many techniques can be implemented. Negotiator may use the right technique or tactics which aim at outcome as close as possible to the assumed goal. Source literature offers information about this field, however, the material is most often described in terms of an individual case. In this paper the author elaborates on and compares different types of techniques and negotiation strategies and suggests the areas and situations in which they may be used at different stages of the negotiation process. The best technic or tactic can be useful for a negotiator and helps him to achieve an object requested