Ferulic acid as a promising candidate for developing selective and effective anti-cancer therapies

Oat hulls contain relatively high amounts of hydroxycinnamic acids, mainly ferulic (4-hydroxy-3-methoxycinnamic) and p-coumaric acids (4-hydroxy-cinnamic), which are inhibitory to cell wall biodegradability by rumen microorganisms. In this paper, a study of the interactive effects of enriched sources of Aspergillus ferulic acid esterase (A-FAE) and Trichoderma xylanase (T-XYL) at different levels on the quantitative release of ferulic acid and p-coumaric acid from oat hulls was carried out. The results show that relative to A-FAE alone, the combined action of A-FAE and T-XYL was superior in causing the release of ferulic acid [up to 41.0% (± 2.1%)], indicating that T-XYL is important in acting with A-FAE in the degradation of feruloyl-polysaccharides of oat hulls. There was no effect of A-FAE alone, but a significant effect of A-FAE in combination with T-XYL on the release of p-coumaric acid from oat hulls. However, there was no extensive release of p-coumaric acid [(maximum release of 9.0% (± 0.7%)] by A-FAE in the presence of T-XYL, indicating a specificity of A-FAE for feruloyl groups, which only efficiently releases ferulic acid and not p-coumaric acid from oat hulls. This study suggests that A-FAE with T-XYL has an interactive effect to be able to break the ester linkage between ferulic acid and the attached sugar, releasing a significant proportion of the ferulic acid from oat hulls. This action, which causes disruption of crosslinks, has the potential to improve hydrolysis of the remaining polysaccharides by rumen microorganisms, which, in turn, would improve rumen degradability of oat hulls. Key words: Ferulic acid esterase, oat hulls, hydroxycinnamic acids, biodegradation

Pseudomonas fluorescens strain FE2 isolated in the presence of ferulic acid was able to grow on hydroxylated and methoxylated compounds bearing the hydroxyl group in the para position. By ethylmethansulphonate (EMS) and transposon mutagenesis, mutants unable to utilize ferulic acid have been selected. The metabolic characterization of the wild-type strain and its mutants indicates that ferulic acid was degraded through the formation of vanillic acid. Mutant FE2B in co-oxidation experiments with glutamate, is able to transform ferulic and dihydroferulic acid into vanillic acid, 4-hydroxycinnamic acid and 3 (4-hydroxyphenyl)-propanoic acid into 4-hydroxybenzoic acid, and 3-hydroxycinnamic acid into 3-hydroxybenzoic acid. The bioconversion of hydroxylated aromatic substrates by the FE2B mutants suggests that the presence of a hydroxyl group on the aromatic ring is required for deacetylase activity.

Emerging evidence suggests that the SAM pointed domain containing ETS transcription factor (SPDEF) plays a significant role in tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there are no in vivo studies with respect to the role of SPDEF in tumor metastasis. The present study examined the effects of SPDEF on tumor cell metastasis using prostate tumor cells as a model. Utilizing two experimental metastasis models, we demonstrate that SPDEF inhibits cell migration and invasion in vitro and acts a tumor metastasis suppressor in vivo. Using stable expression of SPDEF in PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we demonstrate for the first time that SPDEF diminished the ability of disseminated tumors cells to survive at secondary sites and establish micrometastases. These effects on tumor metastasis were not a result of the effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth in vitro or subcutaneous tumor xenograft-growth in vivo. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression. These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo.

Novel synthesis of trans-ferulic acid loaded tragacanth-chitosan nanoformulations and evaluation of their biological activities

Mulberries, Morus spp., grow in different growing regions of Turkey with a high diversity providing an opportunity to select superior accessions. The goal of the study was to determine the differences in phytochemical components and horticultural characteristics between white and black mulberry accessions in the Igdir province. Fruits of black and white mulberries collected from Igdir province were assayed for various horticultural characteristics including berry width, berry length, berry weight, and berry peduncle length. Samples were also assayed for vitamin C, organic acids (citric, tartaric, malic, succinic, and fumaric), sugars (glucose and fructose), phenolic acids (catechin, rutin, quercetin, chlorogenic, ferulic, o-coumaric, p-coumaric, caffeic, syringic, vanillic, and gallic acids), and antioxidant capacity [Trolox equivalent antioxidant capacity (TEAC) assay]. Differences (P < 0.05) were noted between accessions in berry length and berry weight. Malic acid was found to be the predominant organic acid regardless of species. Rutin (for black mulberry) and chlorogenic acid (for white mulberry) were the predominant phenolic acids. Black mulberry had higher glucose and fructose content than white mulberry. Analysis showed that black mulberry had higher content of tartaric acid, malic acid, TEAC, fructose, glucose, catechin, rutin, quercetin, o-coumaric acid, and caffeic acid compared with white mulberry (P < 0.01); however, white mulberry had higher content of succinic acid, vitamin C, chlorogenic acid, ferulic acid, p-coumaric acid, syringic acid, and gallic acid (P < 0.01). Our results provide a reference for further studies of mulberry fruits in detection of organic acids, sugars, antioxidant capacity, and phenolic compounds. Also, it is clear that we need standardized testing, extraction, and analysis protocols to compare genotypes grown in different countries.

Anticancer and antimetastatic potential of enterolactone: Clinical, preclinical and mechanistic perspectives

Cancer disease is a major cause of death in Western societies. Epidemiologically, antioxidant phenols have been associated with diminished incidence of cancer, while experimentally, they have cytotoxic effects on cancer cells. The aim of this study was to clarify whether natural antioxidant phenols render K562 human leukemic cells more susceptible to natural killer (NK) cell apoptosis and/or necrosis. K562 cells were pre-incubated with 7 different phenols (p-hydroxy benzoic acid, syringic acid, ferulic acid, p-coumaric acid, o-coumaric acid, gallic acid, and rutin) individually and afterwards targeted with NK cells at a ratio 1/5. Percentages of apoptotic and necrotic cells were assayed via flow cytometric analysis of annexin V and PI-stained cells. For the morphological assessment, cells were stained with acridine orange and ethidium bromide and were examined under a fluorescence microscope. Pre-treatment with gallic acid significantly rendered K562 cells more susceptible to NK cell-mediated necrosis, while pre-treatment with rutin significantly rendered K562 cells more susceptible to apoptosis. Gallic acid and rutin exert anticarcinogenic activity via the enhancement of K562 cell susceptibility to NK cell-mediated necrosis and apoptosis, respectively.

Separation and quantification of basic hydroxycinnamic amides and hydroxycinnamic acids by reversed-phase high-performance liquid chromatography

Ferulic acid (FA), a phenolic compound abundant in the cell walls of seeds, leaves, and roots of various fruits, vegetables, cereals, and grains, is renowned for its wide range of biological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. Despite its therapeutic potential, the clinical application of FA is hindered by challenges such as poor water solubility, limited bioavailability, rapid metabolism, and instability under physiological conditions. To address these issues, nanotechnology has emerged as a transformative approach, enhancing FA's pharmacokinetic profile. Various nanoparticle-based systems, including polymer-based and lipid-based nanoparticles, have been developed to encapsulate FA. These systems have demonstrated significant improvements in FA's solubility, stability, and bioavailability, with studies showing enhanced antioxidant activity and controlled release profiles. Further, the surface engineering of these nanoparticles provides targeted drug/phytochemical delivery potential. The targeted delivery of drugs/phytochemicals significantly enhances the therapeutic efficacy and minimizes systemic side effects. This review explores the therapeutic potential of FA, the limitations in its clinical application, and the advancements in nanoparticle-based delivery systems that are paving the way for its effective therapeutic use.

Bioactive Peptides in Cancer: Therapeutic Use and Delivery Strategies

Chronic Pancreatitis and Pancreatic Cancer: Prediction and Mechanism

Aromatic compounds are important molecules which are widely applied in many industries and are mainly produced from nonrenewable sources. Renewable sources such as plant biomass are interesting alternatives for the production of aromatic compounds. Ferulic acid and p-coumaric acid, a precursor for vanillin and p-vinyl phenol, respectively, can be released from plant biomass by the fungus Aspergillus niger. The degradation of hydroxycinnamic acids such as caffeic acid, ferulic acid, and p-coumaric acid has been observed in many fungi. In A. niger, multiple metabolic pathways were suggested for the degradation of hydroxycinnamic acids. However, no genes were identified for these hydroxycinnamic acid metabolic pathways. In this study, several pathway genes were identified using whole-genome transcriptomic data of A. niger grown on different hydroxycinnamic acids. The genes are involved in the CoA-dependent β-oxidative pathway in fungi. This pathway is well known for the degradation of fatty acids, but not for hydroxycinnamic acids. However, in plants, it has been shown that hydroxycinnamic acids are degraded through this pathway. We identified genes encoding hydroxycinnamate-CoA synthase (hcsA), multifunctional β-oxidation hydratase/dehydrogenase (foxA), 3-ketoacyl CoA thiolase (katA), and four thioesterases (theA-D) of A. niger, which were highly induced by all three tested hydroxycinnamic acids. Deletion mutants revealed that these genes were indeed involved in the degradation of several hydroxycinnamic acids. In addition, foxA and theB are also involved in the degradation of fatty acids. HcsA, FoxA, and KatA contained a peroxisomal targeting signal and are therefore predicted to be localized in peroxisomes.Key points• Metabolism of hydroxycinnamic acid was investigated in Aspergillus niger• Using transcriptome data, multiple CoA-dependent β-oxidative genes were identified.• Both foxA and theB are involved in hydroxycinnamate but also fatty acid metabolism.

Objective: Lignans are important biologically active compounds in diphenolic structure. Secoisolariciresinol diglucoside (SDG) is a significant type of lignan known to have anti-cancer properties. This study aimed to investigate the antiproliferative activity properties of SDG on hepatocellular carcinoma cells (HepG2), colorectal cancer cells (DLD-1), lung carcinoma (A549), and prostate cancer (PC3) cell lines. Material and Method: Cell viability of cancer cells was determined by the MTT method after treatment with various concentrations of SDG at 48 or 72 hours. The DFT (Density Functional Theory) analysis of the SDG was performed using Spartan'10 and visualized. Drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) properties of this compound were examined. Molecular docking was carried out to research the biological activity of SDG. Result and Discussion: Our results showed that SDG exhibited significant cytotoxicity only against DLD-1 cells with IC50 value of 37.45 µM, but inactive against other cancer cell lines as in vitro. 4UYA, which biomarker for colon cancer, is the crystal structure of the MLK4 kinase domain. The binding energy value for the SDG-MLK4 kinase domain was calculated as -6.1 kcal/mol. Anticancer potential was verified by in vitro assay and in silico molecular docking study. In conclusion, this study revealed the protective aspect of SDG against colon cancer and showed that it has promising anticancer activity.

Up-regulation of the enzymes involved in prostacyclin synthesis via Ras induces vascular endothelial growth factor

Post-translational modification by covalent attachment of isoprenoid lipids (prenylation) regulates the functions and biological activities of several proteins implicated in the oncogenic transformation and metastatic progression of cancer. The largest group of prenylated proteins contains a CAAX motif at the C-terminal that serves as a substrate for a series of post-translational modifications that convert these otherwise hydrophilic proteins to lipidated proteins, thus facilitating membrane association. C17orf37 (chromosome 17 open reading frame 37), also known as C35/Rdx12/MGC14832, located in the 17q12 amplicon, is overexpressed in human cancer, and its expression correlates with the migratory and invasive phenotype of cancer cells. Here we show that C17orf37 contains a functional CAAX motif and is post-translationally modified by protein geranylgeranyltransferase-I (GGTase-I). Geranylgeranylation of C17orf37 at the CAAX motif facilitates association of the protein to the inner leaflet of plasma membrane, enhances migratory phenotype of cells by inducing increased filopodia formation, and potentiates directional migration. A prenylation-deficient mutant of C17orf37 is functionally inactive and fails to trigger dissemination of tail vein-injected cells in a mouse model of metastasis. These findings demonstrate that prenylation is required for the function of the C17orf37 protein in cancer cells and imply that the post-translational modification may functionally regulate metastatic progression of disease.