Molecular basis of the anti-cancer effects of histone deacetylase inhibitors

Histone deacetylase inhibitors comprise a variety of natural and synthetic compounds, which have in common that they inhibit enzymes that mediate the removal of acetyl groups from a range of proteins, including nucleosomal histones. Histone deacetylase inhibitors have anti-cancer activities in vitro and in vivo and are used in the clinic for the treatment of advanced cutaneous T cell lymphoma. The molecular pathways targeted by these compounds are discussed with an emphasis on the effects of these compounds on retinoic acid signaling.     

Restoration of miR-29b exerts anti-cancer effects on glioblastoma

Background

Methylation plays an important role in the etiology and pathogenesis of colorectal cancer (CRC). This study aimed to identify aberrantly methylated-differentially expressed genes (DEGs) and pathways in CRC by comprehensive bioinformatics analysis.

Methods

Data of gene expression microarrays (GSE68468, GSE44076) and gene methylation microarrays (GSE29490, GSE17648) were downloaded from GEO database. Aberrantly methylated-DEGs were obtained by GEO2R. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein–protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. MCODE was used for module analysis of the PPI network.

Results

Totally 411 hypomethylation-high expression genes were identified, which were enriched in biological processes of response to wounding or inflammation, cell proliferation and adhesion. Pathway enrichment showed cytokine–cytokine receptor interaction, p53 signaling and cell cycle. The top 5 hub genes of PPI network were CAD, CCND1, ATM, RB1 and MET. Additionally, 239 hypermethylation-low expression genes were identified, which demonstrated enrichment in biological processes including cell–cell signaling, nerve impulse transmission, etc. Pathway analysis indicated enrichment in calcium signaling, maturity onset diabetes of the young, cell adhesion molecules, etc. The top 5 hub genes of PPI network were EGFR, ACTA1, SST, ESR1 and DNM2. After validation in TCGA database, most hub genes still remained significant.

Conclusion

In summary, our study indicated possible aberrantly methylated-differentially expressed genes and pathways in CRC by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of CRC. Hub genes including CAD, CCND1, ATM, RB1, MET, EGFR, ACTA1, SST, ESR1 and DNM2 might serve as aberrantly methylation-based biomarkers for precise diagnosis and treatment of CRC in the future.

     

Differential effects of anti-cancer and anti-hepatitis drugs on liver cystatin

The drug–protein interaction has been the subject of increasing interest over the decades. In the present communication, the interaction of liver cystatin with anti-cancer (adriamycin) and anti-hepatitis (adevofir dipivoxil) drugs was studied by thiol-protease inhibitory assay, UV absorption, fluorescence spectroscopy and circular dichroism (CD). A static type of quenching was observed between the protein and the drug molecules. Binding constant (Ka) of adriamycin to liver cystatin (LC) was found to be 1.08 × 10⁶ M⁻¹. Moreover, binding site number was found to be 2. Importantly, cystatin loses its activity in the presence of adriamycin. However, intrinsic fluorescence studies in the presence of adevofir dipivoxil showed enhancement in the fluorescence intensity suggesting that binding of adevofir to LC caused unfolding of the protein. The unfolding of the test protein was also accompanied by significant loss of inhibitory activity. CD spectroscopy result showed, both adriamycin and adevofir dipivoxil caused perturbation in the secondary structure of liver cystatin. The possible implications of these results will help in combating drug induced off target effects.Abbreviations: LC, liver cystatin; ADR, adriamycin; CD, circular dichroism; Ka, binding constant; HBV, human hepatitis B virus     

Metabolic effects of dietary fructose

Fructose, a naturally occurring hexose, is a component of many fruits, vegetables, and sweeteners. Because of the introduction of high fructose corn sweeteners in 1967, the amount of free fructose in the diet of Americans has increased substantially in the last 20 years. Fructose is sweeter, more soluble, and less glucogenic than glucose or sucrose, so it has been recommended as a replacement for these sugars in the diets of diabetic and obese people. Although an acute dose of fructose causes smaller increases in glucose and insulin than a comparable dose of glucose, there are a number of changes after dietary adaptation that may reduce its desirability as a sugar replacement in certain segments of the population. Fructose is absorbed primarily in the jejunum and metabolized in the liver. When consumed in excess of dietary glucose, it may be malabsorbed. Fructose is more lipogenic than glucose or starches, and usually causes greater elevations in triglycerides and sometimes in cholesterol than other carbohydrates. Dietary fructose has resulted in increases in blood pressure, uric acid, and lactic acid. People who are hypertensive, hyperinsulinemic, hypertriglyceridemic, non-insulin-dependent diabetic, or postmenopausal are more susceptible to these adverse effects of dietary fructose than healthy young subjects. Although consumption of fructose as a component of fruits and vegetables is an unavoidable consequence of eating a healthy diet, added fructose seems to provide little advantage over other caloric sweetners and compares unfavorably to complex carbohydrates in susceptible segments of the population.     

13,14-Dihydroxy groups are critical for the anti-cancer effects of garcinol

In the presence of K₂CO₃/Cs₂CO₃ (molar ratio 10:1), garcinol was subjected to methylation by reaction with iodomethane at room temperature to afford 13,14-dimethoxy garcinol. The methylated garcinol derivative was screened against oral cancer cell line SCC15 for cell proliferation and apoptosis. 13,14-Dimethoxy garcinol showed weaker inhibitory activity on SCC15 cell growth than garcinol, and had little effect on cell cycle and apoptosis of SCC15, whereas garcinol effectively induced cell cycle arrest and cell apoptosis. Meanwhile, the ELISA data showed that the inhibitory effect of garcinol on 5-Lox pathway was more potent than 13,14-dimethoxy garcinol (P < 0.05). All these results have confirmed the important role of 13,14-dihydroxy groups for anti-cancer effects of garcinol.     

Biological activities of berries: from antioxidant capacity to anti-cancer effects

Consumption of berries has been implicated with diverse health benefits, such as prevention of stroke, of age-related degenerative diseases and cancer. Some berry constituents have been proven to have cancer preventive actions on chemically induced tumors in vivo and cancer suppressive effects in in vitro studies. Many of these effects were attributed to certain berry phytochemicals with high antioxidative potential that could contribute to, or enhance by induction, the endogenous antioxidant properties of living cells or organisms. Producers and the consumers of berry products need more comprehensive and accurate information on the type and level of health benefits that can be expected from different products. The choice of the chemical or biological test that best predicts specific health benefits of berries is crucial to provide targets for berry breeding programmes or to improve processing methods. The aim of this review is to examine the chemical and biological tests developed to characterize the impact of berries on consumer health.     

The effects of the dietary glycemic load on type 2 diabetes risk factors during weight loss

Objective: To compare the effects of two calorie-restricted diets that differ in glycemic load (GL) on glucose tolerance and inflammation. Research Methods and Procedures: Thirty-four healthy overweight adults, ages 24 to 42 years, were randomized to 30% provided calorie-restricted diets with high (HG) or low (LG) glycemic load for 6 months. Outcomes were changes in glucose-insulin dynamics and C-reactive protein (CRP) levels. Results: Compared with baseline, levels of fasting insulin, homeostasis model assessment of insulin resistance, post-load insulin at 30 minutes, and incremental area-under-the-curve-insulin during the oral glucose tolerance test were significantly lower in both groups at 6 months (p range, 0.01 to 0.05), but after adjustment for baseline values and weight change, there were no differences between the two groups with regard to changes over time in any parameter. The mean percentage change in insulin sensitivity by a frequently sampled intravenous glucose tolerance test was +26% in the HG group and +24% in the LG group (p = 0.83); first-phase acute insulin release was −20% in the HG group and −21% in the LG group (p = 0.77). More participants on the LG diet (14 of 16 subjects) had a decline in serum CRP, compared with those on the HG diet (7 of 16 subjects) (p < 0.05). Discussion: In healthy overweight adults provided with food for 6 months, the dietary GL did not seem to influence chronic adaptations in glucose-insulin dynamics above that associated with weight loss. This finding highlights the importance of absolute weight loss over the dietary macronutrient composition used to achieve weight loss. The finding of greater declines in CRP concentration after consumption of a low-GL diet warrants further investigation.     

Cardiovascular effects of dietary copper deficiency

Dietary copper deficiency may impair cardiovascular health by contributing to high blood pressure, enhancement of inflammation, anemia, reduced blood clotting and arteriosclerosis. The purpose of this review is to compile information on the numerous changes of the heart, blood and blood vessels that may contribute to these cardiovascular defects. These alterations include weakened structural integrity of the heart and blood vessels, impairment of the use of energy by the heart, reduced ability of the heart to contract, altered ability of blood vessels to control their diameter and to grow, and altered structure and function of circulating blood cells. The fundamental causes of these changes rest largely on reduced effectiveness of enzymes that depend on copper for their activity.     

The functional genomic studies of resveratrol in respect to its anti-cancer effects

Resveratrol has anti-cancer effects in vitro, and hypothetical chemopreventive effects in vivo. Effects are pleiotropic, mediated by changes in expression of many genes and epigenetic reprogramming. Thus, they are well suited for functional genomic studies. We carried out systematic review of such studies (reflecting also on technological progress). Differentially expressed genes commonly linked to resveratrol treatment were linked to cell cycle, proliferation, and apoptosis. However, it is unclear if these are primary and specific targets of resveratrol. We conclude by discussing areas where additional functional genomic studies are desirable, including experiments that better model in vivo effects of dietary intake.     

Assessment of dietary risk factors in chronic headache

An investigation of the awareness level and potential impact of dietary risk factors on chronic headache patients revealed that (1) approximately 75% of the 130 patients in this study stated they were aware of possible food-intake/headache connections, (2) less than half reported being informed of this relationship by medical professionals, and (3) the awareness of this nutritional information did not prompt changes in subjects' dietary practices. The comparison of food-intake patterns of the headache patients and nonheadache control group revealed a significant difference only on red wine consumption.     

Preclinical evaluation of the imipridone family,analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.     

Preparation of liposomal doxorubicin-graphene nanosheet and evaluation of its in vitro anti-cancer effects

In recent years there has been much interest in development of multifunctional drug delivery systems. In this work, liposomes that contain doxorubicin (Dox), a potent anticancer drug, and graphene nanosheets (GNS) were prepared. The GNSs have excellent optical properties, such as photoluminescence which enables tracking of the liposomes, high absorption in ultra violet region of electromagnetic spectrum which can be exploited in photodynamic and photothermal therapy, and low toxicity to mammalian cells. Nanoliposomes were prepared using the thin film hydration method. Dox and GNSs were loaded to the liposomes during the hydration of the lipid film. Liposomes were characterized and the profile of in vitro drug release, cellular uptake, and cytotoxicity of the prepared liposomes on MCF-7 cells were determined. Despite the earlier reports, the liposomes have kept their spherical structures in the presence of GNSs. The cytotoxicity of liposomal Dox and GNSs were shown to be higher than the free forms of them. Novel nanoliposomes that contain GNSs have provided a multi-functional system with the potential of tracking, photodynamic and photothermal therapy. Further improvements of this versatile nanosystem would be promising for treatment of cancer.     

Assessment of dietary risk factors in chronic headache

An investigation of the awareness level and potential impact of dietary risk factors on chronic headache patients revealed that (1) approximately 75% of the 130 patients in this study stated they were aware of possible food-intake/headache connections, (2) less than half reported being informed of this relationship by medical professionals, and (3) the awareness of this nutritional information did not prompt changes in subjects' dietary practices. The comparison of food-intake patterns of the headache patients and nonheadache control group revealed a significant difference only on red wine consumption.This research was supported in part by a grant from NINCDS, NS-23440.     

Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Drug treatments for HCC have been largely unsuccessful. Histone deacetylase inhibitors can reactivate tumor suppressor genes in cancer cells and serve as potential anti-cancer drugs. Two potent HDAC inhibitors OSU-HDAC42 and SAHA induced autophagy in HCC cells as revealed by transmission electron microscopy, immunofluorescence and LC3-II accumulation. We found that SAHA and OSU-HDAC42 induced autophagy through downregulation of Akt/mTOR signaling and induction of ER stress response. Inhibition of autophagy by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity, indicating that SAHA-induced autophagy led to cell death. Our results show that the combination of autophagy inducers with SAHA might be attractive for the treatment of HCC and pharmacological targeting of autophagy provides promise for the management of cancer therapy.     

Physiological and metabolic effects of dietary fiber

William Beaumont noted the gastric effects of vegetable fiber and suggested that dietary fiber may provide health benefits. In the last decade investigators documented the physiological effects of fiber on gastric emptying, intestinal nutrient absorption rates, and colon function. Further clinical investigation and much more of the type of repetitive observations pioneered by Beaumont are required to definitively establish the physiological effects of fiber on gastrointestinal physiology. High-fiber intake provides well-established benefits for persons with diabetes: it lowers insulin requirements, provides better control of blood glucose, and reduces serum lipids. Foods rich in soluble fiber, such as oat or bean products, lower cholesterol significantly for persons with hypercholesterolemia and for healthy young subjects. High-fiber foods also lower serum triglycerides and blood pressure. Several studies indicate that high intake of fiber protects against coronary heart disease.     

Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Drug treatments for HCC have been largely unsuccessful. Histone deacetylase inhibitors can reactivate tumor suppressor genes in cancer cells and serve as potential anti-cancer drugs. Two potent HDAC inhibitors OSU-HDAC42 and SAHA induced autophagy in HCC cells as revealed by transmission electron microscopy, immunofluorescence and LC3-II accumulation. We found that SAHA and OSU-HDAC42 induced autophagy through downregulation of Akt/mTOR signaling and induction of ER stress response. Inhibition of autophagy by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity, indicating that SAHA-induced autophagy led to cell death. Our results show that the combination of autophagy inducers with SAHA might be attractive for the treatment of HCC and pharmacological targeting of autophagy provides promise for the management of cancer therapy.     

The anti-cancer agent distamycin A displaces essential transcription factors and selectively inhibits myogenic differentiation

A microassay is demonstrated for functional characterization of the Ca2+-release channel (CRC) of sarcoplasmic reticulum (SR) of skeletal muscle using swine with susceptibility to malignant hyperthermia (MH). Diluted muscle homogenates, indo-1 and ratiometric dual-emission spectrofluorometry are used to monitor Ca2+-lowering activity in real-time in the presence and absence of ryanodine at exposures that open and close the CRC. Reactions are initiated with 50 µM CaCl2 to raise ionized Ca2+ concentration near 1 µM and MgATP to activate the Ca2+-ATPase pump. Oxalate is included to precipitate Ca2+ within the SR. The assay requires less than 30 mg muscle, which may be cryopreserved, and is completed within 20 min of thawing the tissue. Maximum SR Ca2+-ATPase pumping and CRC activities, degree of CRC activation, and Ca2+-buffering capacity can be determined. Using this assay we studied muscle from MH-susceptible swine and demonstrated that whereas maximal Ca2+-ATPase pumping and CRC activities are normal, the CRC activity after addition of a bolus of Ca2+ is 50% greater in heterozygotes and 100% greater in homozygotes for the MH mutation. Hypersensitivity to CRC agonists, such as caffeine, and an associated hyposensitivity to CRC antagonists such as Mg2+ is also demonstrated. Genotypes for the MH mutation site can be discriminated from each other by determining Ca2+-lowering activities and the effect of ryanodine on them. (Mol Cell Biochem 167: 61-72, 1997)     

Gut metabotypes govern health effects of dietary polyphenols

1. Download : Download high-res image (292KB)
2. Download : Download full-size image

Highlights► Health effects of dietary polyphenols often depend on multiple metabolic processes. ► Gut metabotypes with specific polyphenol metabolism patterns can be differentiated. ► Physiologically achievable concentrations of relevant metabolites should be tested. ► Novel products and applications can exploit polyphenol–microbiota interactions.