Integrative multi-omics analysis reveals ortho-topolin riboside exhibits anticancer activity by regulating metabolic pathways in radio-resistant triple negative breast cancer cells.

Radio-resistant triple negative breast cancer (TNBC) is resistant to conventional drugs and radiation therapy. ortho-topolin riboside (oTR) has been evaluated for its anticancer activity in several types of cancer cells. However, its anti-proliferative activity in radio-resistant TNBC cells has not yet been reported. Therefore, we investigated the anti-proliferative activity of oTR in radio-resistant TNBC cells, and performed metabolome, lipidome, transcriptome, and proteome profiling to reveal the mechanisms of the anticancer activity of oTR. oTR showed cytotoxicity against radio-resistant TNBC cells with an inhibitory concentration (IC50) value of 7.78 µM. Significantly decreased (p value < 0.05) basal and compensatory glycolysis were observed in the oTR-treated group than untreated group. Mitochondrial spare respiratory capacity, which is relevant to cell fitness and flexibility, was significantly decreased (p value < 0.05) in the oTR-treated group. The major metabolic pathways significantly altered by oTR according to metabolome, transcriptome, and proteome profiles were the glycerolipid/glycerophospholipid pathway (log2(FC) of MGLL = -0.13, log2(FC) of acylglycerol lipase = -1.35, log2(FC) of glycerol = -0.81), glycolysis (log2(FC) of EGLN1 = 0.16, log2(FC) of EGLN1 = 0.62, log2(FC) of glucose = -0.76, log2(FC) of lactate = -0.81), and kynurenine pathway (log2(FC) of KYNU = 0.29, log2(FC) of kynureninase = 0.55, log2(FC) of alanine = 0.72). Additionally, proline metabolism (log2(FC) of PYCR1 = -0.17, log2(FC) of proline = -0.73) was significantly altered in the metabolomic and transcriptomic profiles. The MAPK signaling pathway (log2(FC) of CCN1 = -0.15, log2(FC) of CCN family member 1 = -1.02) and Rap 1 signaling pathway (log2(FC) of PARD6B = -0.28, log2(FC) of PAR6B = -3.13) were also significantly altered in transcriptomic and proteomic profiles. The findings of this study revealed that oTR has anticancer activity in radio-resistant TNBC cells by affecting various metabolic pathways, suggesting the potential of oTR as a novel anticancer agent for radio-resistant TNBC patients.

Melosira nummuloides Ethanol Extract Ameliorates Alcohol-Induced Liver Injury by Affecting Metabolic Pathways.

Melosira nummuloides is a microalga with a nutritionally favorable polyunsaturated fatty acid profile. In the present study, M. nummuloides ethanol extract (MNE) was administered to chronic-binge alcohol-fed mice and alcohol-treated HepG2 cells, and its hepatoprotective effects and underlying mechanisms were investigated. MNE administration reduced triglyceride (TG), total cholesterol (T-CHO), and liver injury markers, including aspartate transaminase (AST) and alanine transaminase (ALT), in the serum of chronic-binge alcohol-fed mice. However, MNE administration increased the levels of phosphorylated adenosine monophosphate-activated protein kinase (P-AMPK/AMPK) and PPARα, which was accompanied by a decrease in SREBP-1; this indicates that MNE can inhibit adipogenesis and improve fatty acid oxidation. Moreover, MNE administration upregulated the expression of antioxidant enzymes, including SOD, NAD(P)H quinone dehydrogenase 1, and GPX, and ameliorated alcohol-induced inflammation by repressing the Akt/NFκB/COX-2 pathway. Metabolomic analysis revealed that MNE treatment modulated many lipid metabolites in alcohol-treated HepG2 cells. Our study findings provide evidence for the efficacy and mechanisms of MNE in ameliorating alcohol-induced liver injury.

Characterization of chemoresistant human non-small cell lung cancer cells by metabolic and lipidomic profiling.

INTRODUCTION: Lung cancer is one of the most malignant cancers and the leading cause of cancer-related deaths worldwide, while acquired chemoresistance would represent a major problem in the treatment of non-small cell lung cancer (NSCLC) because of the reduced treatment effect and increased rates of recurrence. METHODS: To establish the chemoresistant NSCLC cells, doxorubicin was treated to A549 cells over 3 months at gradually increasing concentrations from 0.03 to 0.5 µM. Real-time PCR and Western blotting were employed for investigating mRNA and protein expression of the glutathione peroxidase (GPX) protein family and multidrug resistance protein 1 (MRP1) in A549 and A549/CR cells. We also employed gas chromatography mass-spectrometry and nano electrospray ionization mass-spectrometry coupled with multivariate statistical analysis to characterize the unique metabolic and lipidomic profiles of chemoresistant NSCLC cells in order to identify potential therapeutic targets. RESULTS: Reactive oxygen species levels were decreased, and mRNA and protein levels of GPX2 and multidrug resistance protein 1 (MRP1) were increased in A549/CR. We identified 87 metabolites and intact lipid species in A549 and A549/CR. Among these metabolites, lactic acid, glutamic acid, glycine, proline, aspartic acid, succinic acid, and ceramide, alongside the PC to PE ratio, and arachidonic acid-containing phospholipids were suggested as characteristic features of chemoresistant NSCLC cells (A549/CR). CONCLUSIONS: This study reveals characteristic feature differences between drug-resistance NSCLC cells and their parental cells. We suggest potential therapeutic targets in chemoresistant NSCLC. Our results provide new insight into metabolic and lipidomic alterations in chemoresistant NSCLC. This could be used as fundamental information to develop therapeutic strategies for the treatment of chemoresistant NSCLC patients.

Heptadecanoic Acid, an Odd-Chain Fatty Acid, Induces Apoptosis and Enhances Gemcitabine Chemosensitivity in Pancreatic Cancer Cells.

Odd-chain saturated fatty acids generally serve as specific biomarkers of dietary components and dairy intake, some of which have anticancer properties. This study was performed to assess the anticancer effects of heptadecanoic acid (HDNA) in human pancreatic carcinoma cells. MTT (thiazolyl blue tetrazolium bromide) assay showed that HDNA exerted stronger cytotoxic effects than pentadecanoic acid, palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), and linoleic acid (18:2) on both Panc-1 and MIA PaCa-2 pancreatic cancer cells. In addition, HDNA reduced colony formation and induced apoptosis in these pancreatic cancer cells as indicated by Hoechst 33342 staining, Annexin V/propidium iodide staining, cell cycle analysis, and Western blotting analysis in a dose-dependent manner. Moreover, HDNA synergistically reduced cell viability and promoted apoptosis when combined with gemcitabine (GEM), a chemotherapeutic agent commonly used in the treatment of pancreatic cancer. GEM-resistant MIA PaCa-2 (GR-MIA PaCa-2) cells with a resistance indices (RI) value of 215.09 [RI = half-maximal inhibitory concentration (IC50) of GR-MIA PaCa-2 cells/IC50 of MIA PaCa-2 cells] were established, and the efficacy of HDNA on GEM chemosensitivity was confirmed. Surprisingly, HDNA exhibited even higher antiproliferative efficacy against GR-MIA PaCa-2 cells (IC50 = 71.45 ± 6.37 µM) than parental MIA PaCa-2 cells (IC50 = 77.47 ± 2.10 µM). Finally, HDNA treatment inhibited the Hippo pathway and induced apoptosis of GR-MIA PaCa-2 cells. These findings suggest the beneficial effects of a HDNA-rich diet during pancreatic cancer treatments.

Effects of Combined Pentadecanoic Acid and Tamoxifen Treatment on Tamoxifen Resistance in MCF-7/SC Breast Cancer Cells.

Estrogen receptors are indicators of breast cancer adaptability to endocrine therapies, such as tamoxifen. Deficiency or absence of estrogen receptor α (ER-α) in breast cancer cells results in reduced efficacy of endocrine therapy. Here, we investigated the effect of combined tamoxifen and pentadecanoic acid therapy on ER-α-under-expressing breast cancer cells. Drug resistance gene expression patterns were determined by RNA sequencing analysis and in vitro experiments. For the first time, we demonstrate that the combined treatment of pentadecanoic acid, an odd-chain fatty acid, and tamoxifen synergistically suppresses the growth of human breast carcinoma MCF-7 stem cells (MCF-7/SCs), which were found to be tamoxifen-resistant and showed reduced ER-α expression compared with the parental MCF-7 cells. In addition, the combined treatment synergistically induced apoptosis and accumulation of sub-G1 cells and suppressed epithelial-to-mesenchymal transition (EMT). Exposure to this combination induces re-expression of ER-α at the transcriptional and protein levels, along with suppression of critical survival signal pathways, such as ERK1/2, MAPK, EGFR, and mTOR. Collectively, decreased ER-α expression was restored by pentadecanoic acid treatment, resulting in reversal of tamoxifen resistance. Overall, pentadecanoic acid exhibits the potential to enhance the efficacy of endocrine therapy in the treatment of ER-α-under-expressing breast cancer cells.

Impairment of Glucose Metabolism and Suppression of Stemness in MCF-7/SC Human Breast Cancer Stem Cells by Nootkatone.

Targeting cancer stem cell metabolism has emerged as a promising therapeutic strategy for cancer treatment. Breast cancer stem cells (BCSCs) exert distinct metabolism machinery, which plays a major role in radiation and multidrug resistance. Therefore, exploring the mechanisms involved in energy utilization of BCSCs could improve the effectiveness of therapeutic strategies aimed at their elimination. This study was conducted to clarify the glucose metabolism machinery and the function of nootkatone, a bioactive component of grapefruit, in regulating glucose metabolism and stemness characteristics in human breast carcinoma MCF-7 stem cells (MCF-7SCs). In vivo experiments, transcriptomic analysis, seahorse XF analysis, MTT assay, Western blotting, mammosphere formation, wound healing, invasion assay, flow cytometric analysis, reverse transcription-quantitative polymerase chain reaction, and in silico docking experiments were performed. MCF-7SCs showed a greater tumorigenic capacity and distinct gene profile with enrichment of the genes involved in stemness and glycolysis signaling pathways compared to parental MCF-7 cells, indicating that MCF-7SCs use glycolysis rather than oxidative phosphorylation (OXPHOS) for their energy supply. Nootkatone impaired glucose metabolism through AMPK activation and reduced the stemness characteristics of MCF-7SCs. In silico docking analysis demonstrated that nootkatone efficiently bound to the active site of AMPK. Therefore, this study indicates that regulation of glucose metabolism through AMPK activation could be an attractive target for BCSCs.

Antioxidant activity of banana flesh and antiproliferative effect on breast and pancreatic cancer cells.

Bananas, one of the most widely consumed fruits worldwide, are a rich source of valuable phytochemicals. In this study, the antioxidant and the anticancer potential of banana flesh was investigated. Of the four kinds of banana flesh extracts, the hexane extract (HE) had the highest total polyphenol content (2.54 ± 0.60 mg GAE/g) and total flavonoid content (1.69 ± 0.34 mg RE/g), followed by the chloroform fraction, total ethanol extract, and ethanol fraction. HE was found to exert a strong radical scavenging activity on 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonicacid) (ABTS•) free radicals. According to the IC50 values in various cancer cell lines, HE was found to possess the greatest cell growth inhibitory potential in human pancreatic cancer PANC-1 cells and human triple-negative breast cancer MDA-MB-231 cells. HE induced apoptosis in PANC-1 and MDA-MB-231 cells, as evidenced by the appearance of condensation of chromatin, proteolytic activation of caspase-3 and 7, and increase in the level of the cleaved form of poly (ADP-ribose) polymerase protein. Gas chromatography mass spectrometry (GC-MS) analysis of HE identified several anticancer compounds including palmitic acid, linoleic acid, oleic acid, campesterol, stigmasterol, and γ-sitosterol, supporting the anticancer potential of HE. Our investigation provides a rationale for the use of banana flesh to minimize the risk of cancer-like diseases.

Metabolic and lipidomic characterization of radioresistant MDA-MB-231 human breast cancer cells to investigate potential therapeutic targets.

To provide preliminary insights into metabolic and lipidomic characteristics in radioresistant triple-negative breast cancer (TNBC) cells and suggest potential therapeutic targets, we performed a comprehensive metabolic and lipidomic profiling of radioresistant MDA-MB-231 (MDA-MB-231/RR) TNBC cells and their parental cells using gas chromatography-mass spectrometry and nano electrospray ionization-mass spectrometry, followed by multivariate statistical analysis. Buthionine sulfoximine (BSO) and radiation were co-treated to radioresistant TNBC cells. The level of glutathione (GSH) was significantly increased, and the levels of GSH synthesis-related metabolites, such as cysteine, glycine, and glutamine were also increased in MDA-MB-231/RR cells. In contrast, the level of lactic acid was significantly reduced. In addition, reactive oxygen species (ROS) level was decreased in MDA-MB-231/RR cells. In the lipidomic profiles of MDA-MB-231/RR cells, the levels of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were significantly increased, whereas those of most of the phosphatidylinositol species were significantly decreased. BSO sensitized MDA-MB-231/RR cells to radiotherapy, which resulted in decreased GSH level and increased ROS level and apoptosis. Radioresistant TNBC cells showed distinct metabolic and lipidomic characteristics compared to their parental cells. We suggested activated GSH, PC, and PE biosynthesis pathways as potential targets for treating radioresistant TNBC cells. Particularly, enhanced radiosensitivity was achieved by inhibition of GSH biosynthesis in MDA-MB-231/RR cells.

Ampelopsin Suppresses Stem Cell Properties Accompanied by Attenuation of Oxidative Phosphorylation in Chemo- and Radio-Resistant MDA-MB-231 Breast Cancer Cells.

Ampelopsin, also known as dihydromyricetin, is a commonly found flavonoid in medicinal plants. The cancer stem cell (CSC) population is a promising target for triple-negative breast cancer (TNBC). In this study, flavonoid screening was performed in the established MDA-MB-231/IR cell line, which is enriched in CSCs. Ampelopsin suppressed the proliferation and colony formation of stem cell-rich MDA-MB-231/IR, while inducing their apoptosis. Importantly, ampelopsin displayed an inhibitory impact on the stemness features of MDA-MB-231/IR cells, demonstrated by decreases in mammosphere formation, the CD44+/CD24-/low population, aldehyde dehydrogenase activity, and the levels of stem cell markers (e.g., CD44, MRP1, ß-catenin, and KLF4). Ampelopsin also suppressed the epithelial-mesenchymal transition, as evidenced by decreases in migration, invasion capacity, and mesenchymal markers, as well as an increase in the epithelial marker E-cadherin. Moreover, ampelopsin significantly impaired oxidative phosphorylation by reducing the oxygen consumption rate and adenosine triphosphate production in MDA-MB-231/IR cells. Notably, ampelopsin treatment significantly reduced the levels of the phosphorylated forms of IκBα and NF-κB p65, as well as the levels of tumor necrosis factor (TNF)-α-stimulated phosphorylation of IκBα and NF-κB p65. These results demonstrated that ampelopsin prevents the TNF-α/NF-κB signaling axis in breast CSCs.

Odd-chain fatty acids as novel histone deacetylase 6 (HDAC6) inhibitors.

The dysregulation of histone deacetylases (HDACs) is closely associated with tumorigenesis and has emerged as a promising target for anti-cancer drugs. Some odd-chain fatty acids are present in trace levels in human tissue. Despite limited health benefits, there is increasing experimental evidence of nutritional benefits of odd-chain fatty acids. This study examines the effects of five odd-chain fatty acids (valeric, heptanoic, nonanoic, undecanoic, and pentadecanoic acid) as novel HDAC6 inhibitors. Examination of these fatty acids on the proliferation and clonogenic ability in various cancer cell lines revealed that pentadecanoic and undecanoic acid can strongly inhibit cancer cell proliferation. Heptanoic and nonanoic acid showed moderate anti-proliferative effects, while valeric acid demonstrated weak anti-proliferative effects. HDAC6 inhibitory activities were in the order of pentadecanoic acid (C15:0) > undecanoic acid (C11:0) > nonanoic acid (C9:0) > heptanoic acid (C7:0) > valeric acid (C5:0), consistent with the anti-proliferative assay results. All of these fatty acids promoted the acetylation of α-tubulin in MCF-7 breast and A549 lung cancer cells dose-dependently. In-silico molecular docking analysis showed that increasing the aliphatic carbon chain length facilitates binding to HDAC6 residues, which might be important for the inhibitory potential of HDAC6. This study shows the potential utility of odd-chain fatty acids for epigenetic-based cancer therapy.

Metal-Amino Acid Nanofibers based Triboelectric Nanogenerator for Self-Powered Thioacetamide Sensor.

The biomolecules offer different metal-binding sites to form a coordination polymer with structural diversity. The coordination directed one-dimensional metal-biomolecule nanofibers (Cu-Asp NFs) designed using copper as metal ion and aspartate as a ligand for triboelectric nanogenerator (TENG) is reported here. The different characterization techniques reveal the detailed characteristics of the synthesized Cu-Asp NFs. The robust coating of the Cu-Asp NFs is achieved using a simple tape cast coater. The bending and water dipping studies suggest the stability of the coated material. The relative polarity test and Kelvin probe force microscopy (KPFM) reveal the position of Cu-Asp in the triboelectric series. The Cu-Asp NFs and Teflon are used as the active material for the fabrication of freestanding mode (NF-TENG) and contact-separation mode (cNF-TENG) TENG. The NF-TENG generates an output of 200 V and 6 µA. The simple ion deposition technique enhances the voltage, current, and transferred charge of cNF-TENG by 2.5, 8, and 3 times. The use of the material for the single electrode sliding mode device further confirms the coated material's stability and robustness. A selective self-powered thioacetamide sensor is developed with the cNF-TENG, which exhibits a sensitivity of 0.76 v mM-1. Finally, NF-TENG is demonstrated for powering up numerous portable electronics.

Effects of Cooking and Processing Methods on Phenolic Contents and Antioxidant and Anti-Proliferative Activities of Broccoli Florets.

We investigated the effects of cooking (steaming and microwaving) and processing (freeze-drying and hot-air-drying) methods on the antioxidant activity of broccoli florets. 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•), and alkyl• free radical scavenging assays were employed to assess anti-oxidant potentials. The cytoprotective effect against oxidative damage induced by H2O2 was studied using hepatocellular carcinoma (HepG2) cells. Anti-proliferative effects were assessed in MCF-7 and MDA-MB-231 breast cancer cells. L-sulforaphane in broccoli extracts was quantified using high-performance liquid chromatography (HPLC). Steam and microwave treatments caused increases in total polyphenol content (TPC), whereas the total flavonoid content (TFC) decreased following steam treatment. A slight increase in TFC was observed in the microwaved samples. Extracts of all broccoli samples showed almost identical radical scavenging and cytoprotective effects. HPLC demonstrated that steamed (3 min)-freeze-dried (F-S3) and microwaved (2 min)-freeze-dried (F-M2) samples exhibited elevated levels of L-sulforaphane. In addition, the F-S3 and F-M2 extracts displayed strong anti-proliferative effects in MCF-7 cells, which correlated with L-sulforaphane content. As we observed no significant decrease in the antioxidant activity of broccoli florets, the cooking and processing methods and conditions studied here are recommended for broccoli.

Catechol enhances chemo­ and radio­sensitivity by targeting AMPK/Hippo signaling in pancreatic cancer cells.

Overcoming chemo­ and radio­resistance is a major challenge in pancreatic cancer treatment. Therefore, there is an urgent need to discover novel therapeutic approaches to avoid chemo­ and radio­resistance in pancreatic cancer. Catechol is a phytochemical found in some fruits and vegetables. A few studies have reported on the potential anticancer effects of pure catechol. The present study aimed to explore the chemo­ and radio­sensitizing effects of catechol in Panc­1 human pancreatic cancer cells. The effects of catechol on Panc­1 cell proliferation, clonogenic survival, invasion, and migration were assessed using MTT, cell migration, and Transwell invasion assays. The chemo­ and radio­sensitizing effects of catechol on Panc­1 cells were evaluated via MTT assay and flow cytometry. Western blotting was conducted to analyze the expression of proteins involved in several mechanisms induced by catechol in Panc­1 cells, including growth inhibition, apoptosis, suppression of epithelial­mesenchymal transition (EMT), and chemo­ and radio­sensitizing activities. The results indicated that catechol inhibited proliferation, promoted apoptosis, and suppressed cell migration, invasion, and EMT in Panc­1 cells in a dose­dependent manner. Catechol treatment also induced the phosphorylation of AMP­activated protein kinase (AMPK) with a concomitant reduction in the expression of Hippo signaling pathway components, including Yes­associated protein, cysteine­rich angiogenic inducer 61, and connective tissue growth factor. In addition, catechol enhanced the chemosensitivity of Panc­1 cells to gemcitabine, a commonly used chemotherapy in pancreatic cancer treatment. A combination of catechol and radiation enhanced apoptosis and increased the expression of two radiation­induced DNA damage markers, p­ATM and p­Chk2. Collectively, the present results demonstrated that catechol, a naturally occurring compound, could suppress the proliferation of pancreatic cancer cells, reduce the expression of EMT­related proteins, and enhance the chemo­ and radio­sensitivity of Panc­1 cells by targeting AMPK/Hippo signaling.

Effect of Roasting and Brewing on the Antioxidant and Antiproliferative Activities of Tartary Buckwheat.

We evaluated the effect of the roasting and brewing conditions of Tartary buckwheat (TB), which is widely used in infusion teas, on its antioxidant and antiproliferative activities in vitro. TB was roasted at 210 °C for 10 min and brewed at a high temperature for a short time (HTST; 85-90 °C, 3 min) or at room temperature for a long time (RTLT; 25-30 °C, 24 h). Roasted TB (RTB) tea brewed at RTLT had the highest total polyphenol content (TPC) and total flavonoid content (TFC) among the four TB teas for different roasting and brewing conditions. Moreover, RTB brewed at RTLT showed the greatest 2,2-diphenyl-1-picrylhydrazyl-, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)-, and alkyl-scavenging activities. The TB tea brewed at RTLT had higher Fe2+-chelating activity than that brewed at HTST, irrespective of roasting. Moreover, RTB tea brewed at RTLT inhibited the proliferation of human pancreatic and breast cancer cells. Overall, RTB-RTLT displayed the largest effect on antioxidant and antiproliferative effects. Finally, rutin was found to possess the most pronounced effect on the antioxidant and antiproliferative activities of the TB teas. These results indicate that the antioxidant and antiproliferative activities of RTB are enhanced by RTLT brewing.

10-Gingerol Targets Lipid Rafts Associated PI3K/Akt Signaling in Radio-Resistant Triple Negative Breast Cancer Cells.

10-gingerol is a major phenolic lipid found in the rhizomes of ginger (Zingiber officinale). Being amphiphilic in nature, phenolic lipids have the ability to incorporate into cell membranes and modulate membrane properties. The purpose of the present study was to evaluate the effects of 10-gingerol on lipid raft/membrane raft modulation in radio-resistant triple negative breast cancer (MDA-MB-231/IR) cells. The effects of 10-gingerol on MDA-MB-231/IR cells' proliferation, clonogenic growth, migration, and invasion were assayed using MTT, colony formation, cell migration, and invasion assays, respectively. Sucrose density gradient centrifugation was used to extract lipid rafts. Western blotting and immunofluorescence were employed to assess the effects of 10-gingerol on lipid raft/membrane raft modulation and lipid rafts-associated PI3K/Akt signaling. Cholesterol measurements were carried out using a commercially available kit. 10-gingerol suppressed the proliferation, migration, invasion, and induced apoptosis through targeting the PI3K/Akt signaling pathway in MDA-MB-231/IR cells. Moreover, 10-gingerol was found to modulate the lipid rafts of MDA-MB-231/IR cells and attenuate the key PI3K/Akt signaling components in lipid rafts. The cholesterol content of the lipid rafts and rafts-resident Akt signaling were also affected by exposure to 10-gingerol. The results of the present study highlight rafts-associated PI3K/Akt signaling as a new target of 10-gingerol in MDA-MB-231/IR cells, thus rationalizing a new rafts-mediated treatment approach for radio-resistant triple negative breast cancer cells.

Pentadecanoic Acid, an Odd-Chain Fatty Acid, Suppresses the Stemness of MCF-7/SC Human Breast Cancer Stem-Like Cells through JAK2/STAT3 Signaling.

Saturated fatty acids possess few health benefits compared to unsaturated fatty acids. However, increasing experimental evidence demonstrates the nutritionally beneficial role of odd-chain saturated fatty acids in human health. In this study, the anti-cancer effects of pentadecanoic acid were evaluated in human breast carcinoma MCF-7/stem-like cells (SC), a cell line with greater mobility, invasiveness, and cancer stem cell properties compared to the parental MCF-7 cells. Pentadecanoic acid exerted selective cytotoxic effects in MCF-7/SC compared to in the parental cells. Moreover, pentadecanoic acid reduced the stemness of MCF-7/SC and suppressed the migratory and invasive ability of MCF-7/SC as evidenced by the results of flow cytometry, a mammosphere formation assay, an aldehyde dehydrogenase activity assay, and Western blot experiments conducted to analyze the expression of cancer stem cell markers-CD44, ß-catenin, MDR1, and MRP1-and epithelial-mesenchymal transition (EMT) markers-snail, slug, MMP9, and MMP2. In addition, pentadecanoic acid suppressed interleukin-6 (IL-6)-induced JAK2/STAT3 signaling, induced cell cycle arrest at the sub-G1 phase, and promoted caspase-dependent apoptosis in MCF-7/SC. These findings indicate that pentadecanoic acid can serve as a novel JAK2/STAT3 signaling inhibitor in breast cancer cells and suggest the beneficial effects of pentadecanoic acid-rich food intake during breast cancer treatments.

Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin.

Resistance to chemotherapy and radiation therapy is considered a major therapeutic barrier in breast cancer. Cancer stem cells (CSCs) play a prominent role in chemo and radiotherapy resistance. The established chemo and radio-resistant triple-negative breast cancer (TNBC) cell line MDA-MB-231/IR displays greater CSC characteristics than the parental MDA-MB-231 cells. Escalating evidence demonstrates that metadherin (MTDH) is associated with a number of cancer signaling pathways as well as breast cancer therapy resistance, making it an attractive therapeutic target. Kaplan-Meier plot analysis revealed a correlation between higher levels of MTDH and shorter lifetimes in breast cancer and TNBC patients. Moreover, there was a positive correlation between the MTDH and CD44 expression levels in The Cancer Genome Atlas breast cancer database. We demonstrate that MTDH plays a pivotal role in the regulation of stemness in MDA-MB-231/IR cells. Knockdown of MTDH in MDA-MB-231/IR cells resulted in a reduction in the CSC population, aldehyde dehydrogenase activity, and major CSC markers, including ß-catenin, CD44+, and Slug. In addition, MTDH knockdown increased reactive oxygen species (ROS) levels in MDA-MB-231/IR cells. We found that phenethyl isothiocyanate (PEITC), a well-known pro-oxidant phytochemical, suppressed stemness in MDA-MB-231/IR cells through ROS modulation via the downregulation of MTDH. Co-treatment of PEITC and N-Acetylcysteine (a ROS scavenger) caused alterations in PEITC induced cell death and CSC markers. Moreover, PEITC regulated MTDH expression at the post-transcriptional level, which was confirmed using cycloheximide, a protein synthesis inhibitor.

Annona squamosa L. leaves inhibit alpha-melanocyte-stimulating hormone (α-MSH) stimulated melanogenesis via p38 signaling pathway in B16F10 melanoma cells.

BACKGROUND: Annona squamosa L. is a branched shrub, which is believed to be originated from the America and West Indies. Fruits of this plant are commonly known as custard apple, sugar apple, or sweetsops. A number of studies have proven a range of biological activities associated with various parts of A. squamosa. AIMS: The main aim of the present investigation was to evaluate potential inhibitory effects of A. squamosa leaf extract (ALE) on melanogenesis and its underlying mechanisms in B16F10 murine melanoma cells. METHODS: Inhibitory effects of A. squamosa leaf extract (ALE) on melanogenesis were primarily assessed by determining melanin contents. Effects of ALE on tyrosinase activity and the expression of proteins associated with melanogenesis were then determined. GC-MS analysis was carried out to identify the phytochemical profile of A. squamosa leaf extract. RESULTS: Antimelanogenic effects of ALE were found to exert through the inhibition of melanocyte inducing transcription factor (MITF) and activation of p38. GC-MS analysis identified ent-kaur-16-en-19-ol, 18-oxokauran-17-yl acetate, and ß-sitosterol as major phytochemicals. CONCLUSION: To our knowledge, this is the first study on the antimelanogenic effects of A. squamosa leaves, rationalizing the use A. squamosa leaf extract as a natural depigmentation agent for the treatment of skin diseases and the development of cosmetic products with enhanced skin-lightening capabilities.

Targeting miRNAs by histone deacetylase inhibitors (HDACi): Rationalizing epigenetics-based therapies for breast cancer.

MicroRNAs (miRNAs) belong to a group of short RNA molecules of ~22 nucleotides that play a significant role in the regulation of gene expression through post-transcriptional regulatory mechanisms. They can directly interact with their target mRNA molecules and induce target gene silencing. Many investigations over the past decade have revealed the involvement of different miRNAs in essential biological events. The expression of a considerable number of miRNAs is tightly regulated through epigenetic events such as histone modifications and DNA methylation. Notably, irregularities in these epigenetic events are associated with aberrant expression of miRNAs in a range of diseases including cancer. Impaired epigenetic events associated with aberrant expression of miRNAs can be pharmacologically modified using chromatin modifying drugs. Numerous pre-clinical and clinical data demonstrate that histone deacetylase inhibitors (HDACi) can re-establish the expression of aberrantly expressed miRNAs in a range of cancer types, rationalizing miRNAs as potential drug targets. This review highlights evidence from investigations assessing the effects of different classes of HDACi on miRNA expression in breast cancer (BC).

Changes Over the Fermentation Period in Phenolic Compounds and Antioxidant and Anticancer Activities of Blueberries Fermented by Lactobacillus plantarum.

This study determined the effects of blueberry fermentation by Lactobacillus plantarum on antioxidant and anticancer activities. The fermented blueberries extracted with 80% ethanol (FBE) showed increased superoxide dismutase-like activity, increased scavenging of DPPH and alkyl radicals, and increased antiproliferative activity against human cervical carcinoma HeLa cells by inducing apoptosis. Seven representative phenolic compounds (malvidin 3-O-glucopyranoside, gallic acid, protocatechuic acid, catechol, chlorogenic acid, syringic acid, and epigallocatechin) in FBE were measured by high-performance liquid chromatography at different fermentation times. The content of each phenolic compound in the FBE was dependent on the fermentation period. Protocatechuic acid and catechol levels increased significantly with fermentation time. Of these three major compounds (protocatechuic acid, catechol, and chlorogenic acid), catechol showed the most significant anticancer activity when HeLa cells were treated with each of these three compounds alone or mixed in various ratios. Pearson's product-moment correlation analysis revealed that the increases in antioxidant and anticancer activities following blueberry fermentation were positively correlated with the phenolic acids present in FBE. PRACTICAL APPLICATION: Blueberries fermented with a tannase-producing lactic acid bacteria (LAB), Lactobacillus plantarum showed higher antioxidant activities and antiproliferative activities against human cervical carcinoma HeLa cells than did raw blueberries. L. plantarum fermentation biotransformed blueberry polyphenols into active phenol metabolites with strong antioxidant and antiproliferative activities. Our results suggest that fermented blueberries are rich in phenolic acids, which are a promising source of natural antioxidants and anticancer drugs and can be used as additives in food, pharmaceuticals, and cosmetic preparations.