stilbenes and 3--hydroxypterostilbene

Stilbenes are a class of polyphenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. There are several well-known stilbenes including trans-resveratrol, pterostilbene, and 3'-hydroxypterostilbene. The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health-beneficial effects such as anti-inflammation, -carcinogenic, -diabetes, and -dyslipidemia activities. Moreover, accumulating in vitro and in vivo studies have reported that stilbene compounds act as inducers of multiple cell-death pathways such as apoptosis, cell cycle arrest, and autophagy for chemopreventive and chemotherapeutic agents in several types of cancer cells. The aim of this review is to highlight recent molecular findings and biological actions of trans-resveratrol, pterostilbene, and 3'-hydroxypterostilbene.

Topics: Apoptosis; Humans; Resveratrol; Stilbenes

A natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3'-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell lines; however, the inhibitory effects of HPSB on skin carcinogenesis remains unclear.. The aim of this study was to evaluate the inhibitory effects of HPSB on two-stage skin carcinogenesis in mice and its potential mechanism.. This study investigated the anti-inflammatory and anti-tumor effects of HPSB in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated acute skin inflammation and 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced two-stage skin carcinogenesis model. In addition, the effects of HPSB on the modulation of the phase I and phase II metabolizing enzymes in the DMBA-induced HaCaT cell model were investigated.. The results provide evidence that topical treatment with HPSB significantly inhibits TPA-induced epidermal hyperplasia and leukocyte infiltration through the down-regulation of cyclooxygenase-2 (COX-2), matrix metalloprotein-9 (MMP-9), and ornithine decarboxylase (ODC) protein expression in mouse skin. Furthermore, HPSB suppresses DMBA/TPA-induced skin tumor incidence and multiplicity via the inhibition of proliferating cell nuclear antigen (PCNA), Cyclin B1 and cyclin-dependent kinase 1 (CDK1) expression in the two-stage skin carcinogenesis model. In addition, pretreatment with HPSB markedly reduces DMBA-induced cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) gene expression in human keratinocytes; however, HPSB does not significantly affect the gene expression of the phase II enzymes.. This is the first study to show that topical treatment with HPSB prevents mouse skin tumorigenesis. Overall, our study suggests that natural HPSB may serve as a novel chemopreventive agent capable of preventing carcinogen activation and inflammation-associated tumorigenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Carcinogens; Cyclooxygenase 2; Drug Eruptions; Female; Gene Expression Regulation; Humans; Keratinocytes; Mice, Inbred ICR; Ornithine Decarboxylase; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate

Epidemiological surveys show that obesity and the western diet increase the risk of colitis. Studies have also confirmed that the high-fat-diet (HFD) promoted the deterioration of colitis-related indicators in mice. Compared with stilbenoids, the results showed that 3'-hydroxypterostilbene (HPSB) was found to be the most effective inhibitor for the antiadipogenesis and anti-inflammation. However, its role in ameliorating obesity-promoted colitis is still unknown. We intend to investigate the protective effect and related molecular mechanisms of HPSB on HFD promoted dextran sodium sulfate (DSS)-induced colitis in mice. The results indicate that colitis in the HFD+DSS group tends to be more apparent in the DSS-only group, while feeding 0.025% of HPSB at different stages can improve the colitis induced by HFD+DSS. HPSB significantly reduced the levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) induced by HFD+DSS in mice. Furthermore, the Western blotting revealed that the administration of HPSB significantly downregulated cyclooxygenase-2 (COX-2), plasmalemma vesicle-associated protein-1 (PV-1), and phospho-signal transducer and activator of transcription 3 (p-STAT3) expressions in HFD+DSS treated mice. Presented results reveal that HPSB is a novel functional agent capable of preventing HFD exacerbated colitis.

Topics: Animals; Anti-Inflammatory Agents; Chemokine CCL2; Colitis; Dextran Sulfate; Diet, High-Fat; Disease Models, Animal; Humans; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Obesity; STAT3 Transcription Factor; Stilbenes

3'-Hydroxypterostilbene (trans-3,5-dimethoxy-3',4'-hydroxystilbene) presents in Sphaerophysa salsula, Pterocarpus marsupium, and honey bee propolis and has been reported to exhibit several biological activities. Herein, we aimed to explore the chemopreventive effects of dietary 3'-hydroxypterostilbene and underlying molecular mechanisms on colitis-associated cancer using the azoxymethane (AOM)/dextran sodium sulfate (DSS) model. 3'-Hydroxypterostilbene administration effectively ameliorated the colon shortening and number of tumors in AOM/DSS-treated mice (3.2 ± 1.2 of the high-dose treatment versus 13.8 ± 5.3 of the AOM/DSS group, p < 0.05). Molecular analysis exhibited the anti-inflammatory activity of 3'-hydroxypterostilbene by a significant decrease in the levels of inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-6 (IL-6) (p < 0.05). Moreover, dietary 3'-hydroxypterostilbene also significantly diminished IL-6/signal transducer and activator of transcription signaling and restored colonic suppressor of cytokine signaling 3 levels in the colonic tissue of mice (p < 0.05). Collectively, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary 3'-hydroxypterostilbene against colitis-associated colonic tumorigenesis.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Colitis; Colonic Neoplasms; Cyclooxygenase 2; Disease Models, Animal; Humans; Interleukin-6; Male; Mice; Mice, Inbred ICR; Signal Transduction; STAT3 Transcription Factor; Stilbenes

3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

Topics: Administration, Oral; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Humans; Lactation; Plant Extracts; Pregnancy; Pterocarpus; Rats; Reproduction; Stilbenes

Delineate the selected pharmacodynamics of a naturally occurring stilbene 3'-Hydroxypterostilbene.. Characterize for the first time the pharmacodynamics bioactivity in several in-vitro assays with relevant roles in heart disease, inflammation, cancer, and diabetes etiology and pathophysiology.. 3'-Hydroxypterostilbene was studied in in-vitro assays to identify possible bioactivity.. 3'-Hydroxypterostilbene demonstrated anti-oxidant, anti-inflammatory, cytotoxic, anti-adipogenic, histone deacetylase, and sirtuin-1 inhibitory activity.. The importance of understanding individual stilbene pharmacologic activities were delineated. Small changes in chemical structure of stilbene compounds result in significant pharmacodynamic differences. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Histone Deacetylases; Humans; Mice; Neoplasms; Sirtuin 1; Stilbenes

Here we report that 3'-hydroxypterostilbene (HPSB), a natural pterostilbene analogue, was more potent than pterostilbene against the growth of human cancer cells (COLO 205, HCT-116, and HT-29) with measured IC50 values of 9.0, 40.2, and 70.9 µM, respectively. We found that HPSB effectively inhibited the growth of human colon cancer cells by inducing apoptosis and autophagy. Autophagy occurred at an early stage and was observed through the formation of acidic vesicular organelles and microtubule-associated protein 1 light chain 3-II production. At the molecular levels, the results from western blot analysis showed that HPSB significantly down-regulated phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signalings including decreased the phosphorylation of mammalian target of rapamycin (mTOR). Significant therapeutic effects were demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with HPSB (10 mg/kg i.p.). These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of cyclooxygenase-2 (COX-2), matrix metallopeptidase-9 (MMP-9), vascular endothelial growth factor (VEGF), and cyclin D1, as well as by the induction of apoptosis in colon tumors. Our findings suggest that HPSB could serve as a novel promising agent for colon cancer treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Cyclin D1; Cyclooxygenase 2; Humans; Inhibitory Concentration 50; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinase; Stilbenes; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

A high-performance liquid chromatographic method was developed for the analysis of 3'-hydroxypterostilbene. This method involves the use of a Luna C(18) column with ultraviolet detection at 325 nm. The mobile phase consisted of acetonitrile, water and formic acid (50:50:0.01, v/v/v) with a flow rate of 0.8 mL/min. The calibration curves were linear over the range 0.5-100.0 microg/mL. The mean extraction efficiency was between 97.40 and 111.16%. The precision of the assay was 0.196-14.39% (RSD%), and within 15% at the limit of quantitation (0.5 microg/mL). The bias of the assay was <16% and within 15% at the limit of quantitation. This assay was successfully applied to pre-clinical pharmacokinetic samples from rat urine and serum.

Topics: Animals; Chromatography, High Pressure Liquid; Drug Stability; Linear Models; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Stilbenes

Pterostilbene and 3,5-hydroxypterostilbene are the natural 3,5-dimethoxy analogs of trans-resveratrol and piceatannol, two compounds which can induce apoptosis in tumor cells. In previous studies we demonstrated the importance of a 3,5-dimethoxy motif in conferring pro-apoptotic activity to stilbene based compounds so we now wanted to evaluate the ability of pterostilbene and 3,5-hydroxypterostilbene in inducing apoptosis in sensitive and resistant leukemia cells. When tested in sensitive cell lines, HL60 and HUT78, 3'-hydroxypterostilbene was 50-97 times more potent than trans-resveratrol in inducing apoptosis, while pterostilbene appeared barely active. However, both compounds, but not trans-resveratrol and piceatannol, were able to induce apoptosis in the two Fas-ligand resistant lymphoma cell lines, HUT78B1 and HUT78B3, and the multi drug-resistant leukemia cell lines HL60-R and K562-ADR (a Bcr-Abl-expressing cell line resistant to imatinib mesylate). Of note, pterostilbene-induced apoptosis was not inhibited by the pancaspase-inhibitor Z-VAD-fmk, suggesting that this compound acts through a caspase-independent pathway. On the contrary, 3'-hydroxypterostilbene seemed to trigger apoptosis through the intrinsic apoptotic pathway: indeed, it caused a marked disruption of the mitochondrial membrane potential delta psi and its apoptotic effects were inhibited by Z-VAD-fmk and the caspase-9-inhibitor Z-LEHD-fmk. Moreover, pterostilbene and 3'-hydroxypterostilbene, when used at concentrations that elicit significant apoptotic effects in tumor cell lines, did not show any cytotoxicity in normal hemopoietic stem cells. In conclusion, our data show that pterostilbene and particularly 3'-hydroxypterostilbene are interesting antitumor natural compounds that may be useful in the treatment of resistant hematological malignancies, including imatinib, non-responsive neoplasms.

Topics: Apoptosis; Cell Line, Tumor; fas Receptor; Genes, abl; Genes, MDR; Humans; Leukemia; Phenols; Stilbenes