Resveratrol Analogues Research Articles

P53-dependent downregulation of hTERT protein expression and telomerase activity induces senescence in lung cancer cells as a result of pterostilbene treatment

Cellular senescence is characterized by permanent cell cycle arrest, triggered by a variety of stresses, such as telomerase inhibition, and it is recognized as a tumor-suppressor mechanism. In recent years, telomerase has become an important therapeutic target in several cancers; inhibition of telomerase can induce senescence via the DNA damage response (DDR). Pterostilbene (PT), a dimethyl ether analog of resveratrol, possesses a variety of biological functions, including anticancer effects; however, the molecular mechanisms underlying these effects are not fully understood. In this study, we investigated the possible mechanisms of PT-induced senescence through telomerase inhibition in human non-small cell lung cancer cells and delineated the role of p53 in senescence. The results indicated that PT-induced senescence is characterized by a flattened morphology, positive staining for senescence-associated-β galactosidase activity, and the formation of senescence-associated heterochromatic foci. Telomerase activity and protein expression was significantly decreased in H460 (p53 wild type) cells compared with H1299 (p53 null) cells and p53 knockdown H460 cells (H460-p53-). A more detailed mechanistic study revealed that PT-induced senescence partially occurred via a p53-dependent mechanism, triggering inhibition of telomerase activity and protein expression, and leading to the DDR, S phase arrest and, finally, cellular senescence. This study is the first to explore the novel anticancer mechanism of PT senescence induction via the inhibition of telomerase in lung cancer cells.

Human skin gene expression: Natural (trans) resveratrol versus five resveratrol analogs for dermal applications

Resveratrol (RV) is a polyphenolic compound naturally produced by plants. Polyphenolic compounds incorporated into medicinal products are beneficial but, RV is rapidly metabolized with an associated decline in biological activity. This study tested RV as the standard and compared five structurally modified RV analogs: butyrate, isobutyrate, palmitoate, acetate, and diacetate (to improve functionality) at 1% concentration(s) for 24 h in epiderm full thickness cultures by gene array/qPCR mRNA analysis. When silent mating type information regulation 2 homolog 1, extracellular elements (collagen1A1, 3A1, 4A1; elastin, tissue inhibitor of matrix metalloproteinase 1, fibrillin 1 laminin beta1 and matrix metalloproteinase 9), anti-aging and aging genes, inflammatory biomarkers (interleukin-1A [IL1A], IL1R2, IL-6 and IL-8), nerve growth factor, and the antioxidants (proliferating cell nuclear antigen, catalase, superoxide dismutase and metallothionein 1H/2H) were evaluated, ranking each from highest-to-lowest for gene expression: butyrate > isobutyrate > diacetate > acetate > palmitoate. This study showed that the butyrate and isobutyrate analogs are more biologically active compared to resveratrol and have potential use in topical applications to improve dermal and other health applications. Impact statement Resveratrol has been reported to have a wide variety of health benefits but its rapid metabolism especially after oral ingestion results in very low bioavailability. Notably, the first human skin gene expression study of resveratrol was not published until 2014. The purpose of this study was to determine if increased stability and biological activity could be obtained by modifying the chemical structure of natural (trans) resveratrol and quantifying human gene expression by qPCR of skin biomarkers that enhance dermal health. Five resveratrol analogs were synthesized that increased their lipophilic index to enhance tissue penetration and augment biological activities on the measured parameters that expand the current knowledge of structure/function relationships. The butyrate and isobutyrate modifications displayed gene expression values significantly above resveratrol and suggest that oral application of these and potentially other resveratrol analogs may yield similar results to improve stability and biological activity to benefit/address various disorders/diseases.

Abstract 252: Resveratrol and pterostibene selectively chemosensitize Burkitt’s lymphoma cells to 5-Fluorouracil

Abstract In the current study, we assess the chemosensitization activity of the naturally occurring polyphenols resveratrol (RES) and pterostilbene (PTER) to 5-Fluorouracil (5-FU) in Burkitt’s B-cell lymphoma. RES is a stilbenoid compound found in a variety of fruits, plants, and nuts. In addition to antioxidant and anti-aging properties, RES has been shown to exhibit significant anti-tumor activity against a variety of malignancies. Since the compound is typically protective of normal cells, its anti-cancer activity makes it a promising candidate as both a chemopreventative nutritional supplement and a chemotherapeutic agent. PTER, an analog of RES, has likewise shown anti-cancer activity. Its therapeutic potential, however, is much less understood. Recent studies have investigated the use of these and other natural compounds in adjuvant chemotherapy strategies, many of which continue to produce underwhelming rates of response. Here, we investigate the chemosensitization capacity of both RES and PTER to 5-FU, a commonly used drug in chemotherapy, in healthy lymphocytes and in Burkitt’s B-cell lymphoma (Raji) cells. MTS assays are used to measure the viability of malignant and normal lymphocytes after 5-FU treatment with or without co-incubation of RES, PTER, or RES/PTER combinations. We find that Raji co-incubation with physiologically relevant concentrations (<10uM) of either RES or PTER significantly increases 5-FU toxicity in Raji cells, with data suggesting PTER to be slightly more effective than RES. Interestingly, RES/PTER combinatorial treatments further increase chemosensitization, an important finding considering the typically low bioavailability of each individual compound in vivo. Together, these data support the potential use of RES as a chemosensitizing adjuvant and provide new evidence that its analog, PTER, also possesses significant chemosensitization capacity. Furthermore, our studies suggest that low physiological concentrations of PTER and RES may be still be sufficient to induce significant anti-cancer effects. Citation Format: Connor J. Peck, Michelle H. Townsend, Kim L. O'Neill. Resveratrol and pterostibene selectively chemosensitize Burkitt’s lymphoma cells to 5-Fluorouracil [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 252. doi:10.1158/1538-7445.AM2017-252

Abstract 1053: Synergistic anticancer effects of combined γ-tocotrienol and pterostilbene is associated with a suppression in Rac1/WAVE 2 signaling in highly malignant breast cancer cells

Abstract Breast cancer is the most common cancer and the second leading cause of cancer death in American women. Rho GTPases play a crucial role in regulating different cellular functions, including cell proliferation, gene expression, cell morphology, actin polymerization, cell motility, metastasis and apoptosis. Wiskott-Aldrich syndrome protein family verprolin-homologous protein2 (WAVE2) is a member within the Wiskott-Aldrich syndrome protein (WASP) family displays a significant role in actin polymerization and cytoskeletal organization which, are essential for cellular migration and invasion. γ-Tocotrienol is a natural isoform within the vitamin E family that displays anticancer activity against a variety of cancer cell types. Pterostilbene is a natural dimethyl ether analog of resveratrol that has several beneficial effects such as anticancer activity. Studies were conducted to examine the effects of combined γ-tocotrienol and pterostilbene on Rac1/WAVE 2 signaling in mouse +SA and human MDA-MB231 breast cancer cells and cellular migration. Results show that combined treatment of γ-tocotrienol and pterostilbene caused a synergistic inhibition of both mouse +SA and human MDA-MB231 breast cancer cells growth, and corresponding reduction in Rac1/WAVE2 signaling as characterized by a significant inhibition in the levels of phospho-Rac1/cdc42, WAVE2, Arp2, and Arp3 expression. Additional studies indicated that this combination resulted in a significant inhibition in mammary cancer cell migration. In summary, these findings strongly suggest that combined treatment of γ-tocotrienol with pterostilbene may provide great benefit as a therapeutic approach in the treatment of metastatic breast cancer. Supported by a grant from the Louisiana Cancer Foundation. Citation Format: Ibrahim G. Algayadh, Paul William Sylvester. Synergistic anticancer effects of combined γ-tocotrienol and pterostilbene is associated with a suppression in Rac1/WAVE 2 signaling in highly malignant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1053. doi:10.1158/1538-7445.AM2017-1053

HS-1793, a resveratrol analogue, downregulates the expression of hypoxia-induced HIF-1 and VEGF and inhibits tumor growth of human breast cancer cells in a nude mouse xenograft model.

A synthetic analogue of resveratrol, 4-(6-hydroxy-2-naphtyl)-1,3-benzenediol(HS-1793), with improved photosensitivity and stability profiles, has been recently reported to exert anticancer activity on various cancer cells. However, the molecular mechanism of action and invivo efficacy of HS-1793 in breast cancer cells have not been fully investigated. In the present study, we evaluated the effect of HS-1793 on hypoxia-inducible factor-1α(HIF-1α), which drives angiogenesis and the growth of solid tumors, in addition to the invivo therapeutic effects of HS-1793 on breast cancer cells. HS-1793 was found to inhibit hypoxia (1.0% oxygen)-induced HIF-1α expression at the protein level, and its inhibitory effect was more potent than that of resveratrol in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, HS-1793 reduced the secretion and mRNA expression of vascular endothelial growth factor(VEGF), a key mediator of HIF-1-driven angiogenesis, without affecting cell viability. To evaluate the anticancer effects of HS-1793 invivo, triple-negative MDA-MB-231 breast cancer xenografts were established in nude mice. HS-1793 significantly suppressed the growth of breast cancer tumor xenografts, without any apparent toxicity. Additionally, decreases in Ki-67, a proliferation index marker, and CD31, a biomarker of microvessel density, were observed in the tumor tissue. Expression of HIF-1 and VEGF was also downregulated in xenograft tumors treated with HS-1793. These invivo results reinforce the improved anticancer activity of HS-1793 when compared with that of resveratrol. Overall, the present study suggests that the synthetic resveratrol analogue HS-1793 is a potent antitumor agent that inhibits tumor growth via the regulation of HIF-1, and demonstrates significant therapeutic potential for solid cancers.

P 053 - Piceatannol exerts anti-obesity effect through modulating adipogenic proteins and gut microbiota in C57BL/6 mice

Obesity is a global health concern. Piceatannol (Pic), an analog of resveratrol (Res), has lots of biological actives. In this study, we investigated the anti-obesity effect of Pic in the high-fat diet (HFD) induced obese animal model. The results showed that Pic significantly reduced mice body weight in a dose-dependent manner without affecting food intake. Pic significantly decreased the weight of liver, spleen, perigonadal and retroperitoneal fat compared with HFD group. Pic significantly reduced the cell size of perigonadal fat and decreased in both the size and number of lipid droplets accumulated in the liver. Pic-treated mice showed higher phosphorylatedadenosine 5´-monophosphate-activated protein kinase (pAMPK) and phosphorylated acetyl-CoA carboxylase (pACC) expression and decreased expression of CCAAT/enhancer-binding proteins (C/EBP) α, peroxisome proliferators activated receptors (PPAR) γand (FAS) , resulted in decreased lipid accumulation tin adipocyte and liver. Although, HFD group had lower Firmicutes (F)/Bacteroidetes (B) ratio, but Pic could increase Lactobacillus and Clostridiales and decreased Sphingobacteriales compared with HFD group. Collectively, these results suggested that Pic could be a candidate for obesity treatment.

Impact of resveratrol analogues on a 3D in vitro model of human skin

Impact of resveratrol analogues on a 3D in vitro model of human skin

Pterostilbene alleviates polymicrobial sepsis-induced liver injury: Possible role of SIRT1 signaling

Liver injury occurs frequently during sepsis. Pterostilbene (Pte), a natural dimethylated analog of resveratrol from blueberries, exerts anti-inflammatory and anti-apoptotic effects in various diseases. However, the role of Pte in sepsis-induced liver injury and its underlying mechanisms remain unknown. The current study aimed to evaluate the protective effects of Pte on sepsis-induced liver injury and its potential mechanisms. Sepsis was induced using cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were administered Pte (5, 10, 15mg/kg, i.p.) at 0.5h, 2h, and 8h after CLP induction. The pathological changes of the liver were evaluated using hematoxylin and eosin (H&E) staining. The serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), myeloperoxidase (MPO), p38 mitogen-activated protein kinase (p38MAPK), Bax, and B-cell lymphoma 2 (Bcl-2) were also evaluated. Pte treatment attenuated the CLP-induced liver injury, as evidenced by the attenuated histopathologic injuries and the decreased serum aminotransferase levels. Pte reduced the serum inflammatory cytokine (TNF-α and IL-6) levels and hepatic mRNA levels of TNF-α and IL-6. Pte also reduced MPO activity and p38MAPK activation in the liver. Additionally, Pte significantly inhibited Bax expression and increased Bcl-2 expression. Moreover, Pte increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). However, SIRT1 small interfering RNA (siRNA) abolished Pte's effects on the expression levels of those protein. Notably, Pte improved the survival rate in septic mice. In conclusion, Pte alleviates sepsis-induced liver injury by reducing inflammatory response and inhibiting hepatic apoptosis, and the potential mechanism is associated with SIRT1 signaling activation.

Development and validation of HPLC-MS/MS procedure for determination of 3,4,4',5-tetra-methoxystilbene (DMU-212) and its metabolites in ovarian cancer cells and culture medium.

The synthetic resveratrol analogue DMU-212 (3,4,4',5-tetramethoxystilbene) has been shown to possess stronger anticancer activity than resveratrol in a variety of tumour cells. To date, there has been no appropriate procedure that would ensure a reliable data about levels of metabolic products of DMU-212 in cancer cell lines. The purpose of this study was to develop a new procedure for determination of DMU-212 and its three metabolites (DMU-214, DMU-281, DMU-291) in cell lines. Analyses were performed using an HPLC system coupled with a triple quadrupole mass spectrometer operating in multiple reaction monitoring mode. Separation was conducted using a C18 column at a flow rate 800μL/min with a mobile phase consisting of 5mM ammonium acetate with 0.1% formic acid (solvent A) and acetonitrile (solvent B). The new methodology is fast, simple and has excellent specificity. Moreover, it showed good linearity in two matrices - cell lysates and culture media. Accuracy values for analytes evaluated at different concentration levels ranged from 0.43 to 18% (%bias). The intra-day and inter-day precision, expressed as CV, was in a range 0.49-5.5% and 0.83-13%, respectively. The validated procedure was successfully applied to quantify the resveratrol analogues in the human ovarian cancer cell line SKOV3.

MED28 Regulates Proinflammatory Cytokine‐induced Epithelial–Mesenchymal Transition and Invasion in Human Breast Cancer Cells

MED28, one of the Mediator subunits, exhibits multiple cellular roles, including involved in transcriptional activation and as a merlin, Grb2, and cytoskeleton‐associated protein, which is highly expressed in several types of malignancy including breast and colorectal tumors. Chronic inflammation, as suggested as one of the hallmarks of cancer, may promote carcinogenesis. Inflammatory cytokines such as tumor necrosis factor‐alpha (TNFα) may mediate tumor initiation, promotion, and progression. Recently, we have identified that MED28 is involved in regulating cell growth, epithelial–mesenchymal transition (EMT), and migration in human breast cancer cells. The objective of this study is to investigate if MED28 is involved in the proinflammatory cytokine‐induced EMT in human breast cancer cells. In aggressive MDA‐MB‐231 cells, MED28 suppression attenuated the mesenchymal morphology and reduced the expression of several mesenchymal biomarkers; however, MED28 overexpression exhibited a reciprocal effect. In addition, TNFα upregulated the expression of the target genes of NFκB/p65 and enhanced an even more aggressive phenotype, whereas suppression of MED28 attenuated the effect. Moreover, pterostilbene, a resveratrol analogue, suppressed the expression of MED28, p‐p65, and p65 downstream target genes, which warrants further investigation for a putative translational application in breast cancer.Support or Funding InformationThis work was supported by the grants NSC102‐2320‐B‐309‐001‐MY3 and MOST105‐2320‐B‐309‐001 to M‐F Lee and MOST103‐2815‐C‐309‐012‐B to C‐I Li.

Piceatannol May Slow Cancer Cachexia‐Induced Weight‐Loss In Vivo

Cancer‐associated cachexia (CAC) is the ongoing loss of lean muscle and adipose that results in functional impairment. CAC reduces chemotherapy effectiveness, lowers quality of life, and is considered the direct cause of death in up to 20% of all cancer mortalities. Strategies that preserve body weight can improve survival and quality of life. Recent reports indicate that preserving adipose mass, specifically, is a key strategy to protect body weight and increase survival in CAC. Piceatannol is resveratrol analog with anti‐inflammatory and anti‐adipogenic properties. We recently demonstrated that piceatannol, unlike resveratrol, inhibits lipolysis, the main mechanism of adipose loss in CAC, in cancer‐associated conditions in vitro. In this study, we evaluated piceatannol's effect in tumor‐induced weight loss. Five‐week‐old female BALB/c mice were inoculated with C26 colon carcinoma cells, an established model of CAC wasting. Following tumor establishment, mice received daily piceatannol injection for two weeks. Piceatannol treatment showed a strong trend in protecting against tumor‐induced weight loss and wasting. The effect of piceatannol appeared to be independent of tumor growth, as no difference in tumor size and volume was detected between piceatannol‐treated and vehicle‐treated tumor‐bearing mice. In addition, mice receiving piceatannol treatment exhibited higher serum triglycerides than vehicle‐treated tumor‐bearing mice. Dual‐energy X‐ray absorptiometry revealed a trend for preserved lean muscle in piceatannol‐treated mice with little effect on fat mass. This study lays the foundation for the use of piceatannol, a natural small‐molecule, in the preservation of body weight in CAC.Support or Funding InformationNIH, 5R03CA184544‐01A1 and U.S. Department of Agriculture National Needs Fellowship

Synthesis and Biological Evaluation of Styrylheterocycles Analogs of Resveratrol as Apoptosis-Inducing Agents

Background: Apoptosis is a route of cell death induced by a highly regulated intracellular program. An increase in apoptotic activity could lead to neurodegenerative pathologies, whereas a decrease in apoptotic activity could lead to uncontrolled cellular proliferation. Keywords: Styrylheterocycles, 2-thienyl-styrenes, 3-thienyl-styrenes, apoptosis, cytotoxicity, U-937 cell line.

Atomic 3D-QSAR study based on pharmacophore modeling of resveratrol derivatives as selective COX-2 inhibitors

This work, based on pharmacophore modeling, aimed to elucidate the three-dimensional structural features of resveratrol derivatives by generating the three-dimensional common pharmacophore responsible for the binding to the inflammation-inducible target. A five points pharmacophore, with three hydrogen bond acceptors and two aromatic rings as pharmacophoric features, was developed. The fit values of the generated pharmacophore are high, except for the Resv34 compound, which could be due to its lowest activity toward cyclooxygenase-2. This pharmacophore yielded a statistically significant atom-based three-dimensional-quantitative structure–activity relationships model with values of R 2, F and standard deviation of 0.9735, 165.4, and 0.2058, respectively, for a training set of twenty-three molecules. Obtained data for a test set of nine compounds with 0.9343, 0.3676, and 0.9694 values for correlation coefficient Q 2, root-mean-square error and Pearson R, respectively, suggested an excellent predictive power of the model. Further, the visualization of the three-dimensional-quantitative structure–activity relationships model provided information about the structure–activity relationships by revealing the importance of electron withdrawing and hydrophobic features, on the chemical structure of compounds for the inhibition of cyclooxygenase-2 enzyme activity. The model therefore provides explicit advances for the design of better resveratrol analogs as cyclooxygenase-2 inhibitors. Thus, the obtained three-dimensional-quantitative structure–activity relationships model can predict novel compounds derived from the low active resveratrol analogs, with improved structures, allowing them to have a better inhibitory effect toward cyclooxygenase-2.

Pterostilbene, a dimethylated analog of resveratrol, promotes energy metabolism in obese rats

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol and has been reported to exert various pharmacological effects. In this study, we evaluated the effect of pterostilbene on the pathogenesis of obesity and energy metabolism in obese rats.Pterostilbene significantly activates silent mating type information regulation 2 homolog-1 and peroxisome proliferator-activated receptor-alpha in vitro. At 4 weeks a 0.5% pterostilbene diet markedly suppressed the abdominal white adipose tissue (WAT) accumulation in obese rats. The oxygen consumption and energy expenditure were significantly higher in the pterostilbene group, and pterostilbene increased the fat metabolism rather than the carbohydrate metabolism in obese rats. The mRNA level of uncoupling protein, a thermogenic regulator, was increased and the mRNA levels of fatty acid synthase and leptin, which are involved in lipogenesis and fat storage, were markedly decreased in WAT after the pterostilbene feeding. These results suggest that pterostilbene prevents WAT accumulation through the enhancement of energy metabolism and partly the suppression of lipogenesis in obese OLETF rats.

Electrochemical Study of Trametes Versicolor Laccase Compatibility to Different Polyphenolic Substrates

The aim of this electrochemical study was to ascertain which position of hydroxy groups on a benzene ring provides electroactive products after enzymatic oxidation by laccase originating from the Trametes versicolor mushroom, exhibiting intense redox signals that are exploitable for their amperometric determination. The electrochemical properties of phenol together with all isomers of benzenediol and cresol at the bare carbon paste electrode (CPE) and CPE modified with enzyme laccase (CPE/Laccase) were investigated using cyclic voltammetry at various scan rates. Comparison of resulting redox signals and their differences confirmed the suitability of classes of polyphenolic compounds as substrates for Trametes versicolor laccase and their potential use as suitable biological components in the development of amperometric enzyme biosensors for the determination of such species. The feasibility of the proposed approach was verified by electrochemical assays of the enzymatic oxidation of polyphenolic analogues of simple phenols, e.g., gentisic acid, caffeic acid, resveratrol, and others.

De novo biosynthesis of pterostilbene in an Escherichia coli strain using a new resveratrol O-methyltransferase from Arabidopsis

BackgroundPterostilbene, a structural analog of resveratrol, has higher oral bioavailability and bioactivity than that of the parent compound; but is far less abundant in natural sources. Thus, to efficiently obtain this bioactive resveratrol analog, it is necessary to develop new bioproduction systems.ResultsWe identified a resveratrol O-methyltransferase (ROMT) function from a multifunctional caffeic acid O-methyltransferase (COMT) originating from Arabidopsis, which catalyzes the transfer of a methyl group to resveratrol resulting in pterostilbene production. In addition, we constructed a biological platform to produce pterostilbene with this ROMT gene. Pterostilbene can be synthesized from intracellular l-tyrosine, which requires the activities of four enzymes: tyrosine ammonia lyase (TAL), p-coumarate:CoA ligase (CCL), stilbene synthase (STS) and resveratrol O-methyltransferase (ROMT). For the efficient production of pterostilbene in E. coli, we used an engineered E. coli strain to increase the intracellular pool of l-tyrosine, which is the initial precursor of pterostilbene. Next, we tried to produce pterostilbene in the engineered E. coli strain using l-methionine containing media, which is used to increase the intracellular pool of S-adenosyl-l-methionine (SAM). According to this result, pterostilbene production as high as 33.6 ± 4.1 mg/L was achieved, which was about 3.6-fold higher compared with that in the parental E. coli strain harboring a plasmid for pterostilbene biosynthesis.ConclusionAs a potential phytonutrient, pterostilbene was successfully produced in E. coli from a glucose medium using a single vector system, and its production titer was also significantly increased using a l-methionine containing medium in combination with a strain that had an engineered metabolic pathway for l-tyrosine. Additionally, we provide insights into the dual functions of COMT from A. thaliana which was characterized as a ROMT enzyme.

Abstract P4-10-03: Pterostilbene enhances TRAIL-induced apoptosis in TRAIL-resistant triple negative breast cancer cells

Abstract Triple-negative breast cancer (TNBC) is refractory to commonly used chemotherapeutic agents, as a result it leads to relatively poor prognosis. TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer. Unfortunately, patients develop resistance to the TRAIL, therefore, agents that can sensitize cells to TRAIL are urgently needed. Pterostilbene (PTER), a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities. In the present study, we investigated whether PTER affect TRAIL-induced apoptosis and its mechanism in TRAIL-resistant TNBC cells. First, our results indicated that PTER induced apoptosis in TNBC BT-20 cells. Next, we found that PTER enhanced TRAIL-induced apoptosis in TRAIL-resistant TNBC BT20 and MDA-MB-468 cells. We demonstrated that PTER induced both death receptor (DR)-5, DR4 and decreased decoy receptor (DcR)-2 expression. PTER also decreased the expression of anti-apoptotic proteins survivin, Bcl-xL and c-FLIPS/L, but had minimal effect on the expression of Bcl-2. PTER caused the cleavage of bid protein and enhanced the expression of pro-apoptotic Bax. Moreover, we found that PTER induced DR4 and DR5 expression through the reactive oxygen species (ROS) –mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen activated protein kinase (p38 MAPK). Overall, our results show that PTER can potentiate TRAIL-induced apoptosis through the ROS–mediated activation of ERK 1/2 and p38 MAPK leading to DR4 and DR5 induction and down-regulation of anti-apoptotic proteins. Citation Format: Wu Y-C, Wang H-C, Chen C-J, Liu L-C, Way T-D. Pterostilbene enhances TRAIL-induced apoptosis in TRAIL-resistant triple negative breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-10-03.

An integral study of cyclodextrins as solubility enhancers of α-methylstilbene, a resveratrol analogue.

trans-α-Methylstilbene (tMS), a resveratrol analogue, has recently been studied in a search for new bioactivities. However, such studies do not take into account that the poor solubility of tMS in aqueous solutions could affect its bioactivity. For this reason, we propose, for the first time, using cyclodextrins (CDs) as solubilizers to increase tMS solubility, in aqueous solutions. The HPLC-RP results obtained, point to a 1 : 1 stoichiometry for all the natural (α-, β- and γ-CD) and modified (HPβCD and MβCD) CDs tested. The KFapp (apparent formation constant) for the tMS-CD complexes was seen to be closely dependent on several factors, including the temperature and type of CD. Indeed, the highest KFapp value was obtained for MβCD, while the KFapp decreased with increasing temperature. In addition, the results showed negative entropy (-8.86 × 10-3 ± 0.40 kJ mol-1 K-1) and enthalpy (-16.70 ± 0.98 kJ mol-1) changes and a negative Gibbs free energy value at 25 °C (-14.00 ± 0.55 kJ mol-1) for the encapsulation process. A computational study carried out using molecular docking calculations showed a high degree of correlation between the computed scores and experimental values. Finally, the complexation of trans-stilbene and pinosylvin with HPβCD was compared with tMS.

Anticancer effects of novel resveratrol analogues on human ovarian cancer cells.

Resveratrol, a naturally occurring phytoalexin, has long been known to play an important regulatory role in key functions in cell physiology. This multifunctional role of resveratrol is explained by its ability to interact with several targets of various cell pathways. In the recent past, synthetic chemical modifications have been made in an attempt to enhance the biological effects of resveratrol, including its anti-cancer properties. In this study, we investigated the molecular mechanisms of action of novel trans-restricted analogues of resveratrol in which the C-C double bond of the natural derivative has been replaced by diaryl-substituted imidazole analogues. In ovarian cancer models, the results of in vitro screening revealed that the resveratrol analogues exhibited enhanced anti-proliferative properties compared with resveratrol. We found that the resveratrol analogues also significantly inhibited Akt and MAPK signalling and reduced the migration of IL-6 and EGF-treated cells. Finally, in ascite-derived cancer cells, we demonstrated that the resveratrol analogues reduced the expression of epithelial mesenchymal transition (EMT) markers. Collectively, these findings indicate the enhanced anti-cancer properties of the resveratrol analogues.

Pterostilbene 4'-β-Glucoside Protects against DSS-Induced Colitis via Induction of Tristetraprolin.

Pterostilbene, a dimethyl ester analog of resveratrol, has anti-inflammatory and antioxidative effects and alters cell proliferation. Tristetraprolin (TTP) promotes the degradation of proinflammatory mediators via binding to adenosine and uridine- (AU-) rich elements (ARE) located in the 3′-untranslated regions of mRNAs. Here, we utilized pterostilbene 4′-β-glucoside (4-PG), a compound derived from pterostilbene, to investigate whether it has anti-inflammatory effects on dextran sulfate sodium- (DSS-) induced colitis via TTP enhancement. TTP expression was increased in 4-PG dose- and time-dependent manners in RAW264.7 cells. The production of proinflammatory cytokine, such as TNF-α, was reduced by 4-PG in vitro. To investigate the role of TTP in the anti-inflammatory effects of 4-PG, we used DSS–induced colitis in TTP WT and KO mice as models. The expression levels of TTP and proinflammatory cytokines were determined in serum and colon tissue. 4-PG increased the expression of TTP while suppressing proinflammatory cytokines both in vitro and in vivo. These findings suggest that treatment with 4-PG mediates the anti-inflammatory effects of 4-PG on DSS-induced colitis via enhancing TTP expression.