stilbenes and Carcinogenesis

Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Autophagy; Carcinogenesis; Cell Cycle; Gene Expression; Humans; Resveratrol; Skin Neoplasms; Stilbenes; Ultraviolet Rays

In past decades, increasing evidence regarding cancer stem cells (CSCs) may account for carcinogenesis, tumor drug-resistant, and metastasis. CSCs are even considered as the root causes of tumor recurrence and metastases. Targeting CSCs may provide a new clue to cure cancer. Epidemiological and clinical studies have suggested that intake of dietary natural products may bring health benefits including lowering risk of cancer incidence. In this review, we have particularly focused on targeting signaling pathways of CSCs by natural resveratrol and its dimethylated derivative pterostilbene. © 2017 BioFactors, 44(1):61-68, 2018.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Carcinogenesis; Cell Communication; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Proteins; Neoplastic Stem Cells; Resveratrol; Signal Transduction; Stilbenes; Xenograft Model Antitumor Assays

Carcinogenesis is a multistep process triggered by genetic alterations that activate different signal transduction pathways and cause the progressive transformation of a normal cell into a cancer cell. Polyphenols, compounds ubiquitously expressed in plants, have anti-inflammatory, antimicrobial, antiviral, anticancer, and immunomodulatory properties, all of which are beneficial to human health. Due to their ability to modulate the activity of multiple targets involved in carcinogenesis through direct interaction or modulation of gene expression, polyphenols can be employed to inhibit the growth of cancer cells. However, the main problem related to the use of polyphenols as anticancer agents is their poor bioavailability, which might hinder the in vivo effects of the single compound. In fact, polyphenols have a poor absorption and biodistribution, but also a fast metabolism and excretion in the human body. The poor bioavailability of a polyphenol will affect the effective dose delivered to cancer cells. One way to counteract this drawback could be combination treatment with different polyphenols or with polyphenols and other anti-cancer drugs, which can lead to more effective antitumor effects than treatment using only one of the compounds. This report reviews current knowledge on the anticancer effects of combinations of polyphenols or polyphenols and anticancer drugs, with a focus on their ability to modulate multiple signaling transduction pathways involved in cancer.

Topics: Acids; Animals; Anthocyanins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Carcinogenesis; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Flavones; Flavonoids; Humans; Isoflavones; Lignans; Mice; Nanotechnology; Neoplasms; Phenols; Phosphorylation; Polyphenols; Rats; Signal Transduction; Stilbenes

Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFα

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Cell Transdifferentiation; Cyclohexylamines; Female; Fibrosis; Hepatic Stellate Cells; Humans; Interleukin-8; Lectins, C-Type; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Mannose Receptor; Mannose-Binding Lectins; Mice; Mice, Inbred C57BL; Myeloid Cells; Neoplasms, Experimental; Oxidative Phosphorylation; Phenotype; Pyrimidines; Receptors, Cell Surface; Signal Transduction; Stilbenes; Syk Kinase; Transcriptome

Coumarins are a wide group of naturally occurring compounds which exhibit a wide range of biological properties such as anti-cancer activities. Here, we characterized the biological functions of three Triphenylethylene-Coumarin Hybrids (TCHs) both in cell culture and nude mouse model.. Cell proliferation assay was performed in the cell cultures of both EA.hy926 endothelial cell and breast cancer cell lines treated with different concentrations of compound TCH-10b, TCH-5a and TCH-5c. Flowcytometry assay and Western blotting were used to further investigate the effect and mechanism of TCH-5c on EA.hy926 cell proliferation and cell cycle. The effects of TCH-5c on endothelial cell migration and angiogenesis were determined using cytoskeleton staining, migration assay and tube formation assay. Inhibition of breast cancer cell line derived VEGF by TCH-5c was shown through ELISA and the use of conditioned media. SK-BR-3 xenograft mouse model was established to further study the anti-tumorigenic role of compound TCH-5c in vivo.. We found that compound TCH-5c has inhibitory effects on both vascular endothelial cells and breast cancer cell lines. Compound TCH-5c inhibited proliferation, resulted in cell death, increased p21 protein expression to induce G0/G1 arrest and changed endothelial cell cytoskeleton organization and migration in EA.hy926 endothelial cells. Compound TCH-5c also inhibited breast cancer cell line derived VEGF secretion, decreased breast cancer cell-induced endothelial cell tube formation in vitro and suppressed SK-BR-3 breast cancer cell-initiated tumor formation in vivo.. Our study demonstrates that the coumarin derivative TCH-5c exerts its anti-cancer effects by 1. inhibiting endothelial cell proliferation, migration. 2. suppressing tube formation and angiogenesis induced by breast cancer cells in vitro and in vivo. Our results have potential implications in developing new approaches against breast cancer.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Breast Neoplasms; Carcinogenesis; Coumarins; Female; Humans; Mice, Nude; Neovascularization, Pathologic; Stilbenes

The combination approach is now a well-established treatment for cancer. The present study evaluated the potential of curcumin and resveratrol on p53 post-translational modifications during gastric cancer. We segregated rats into five groups that included normal controls, dimethylhydrazine (DMH) treated, DMH + curcumin treated, DMH + resveratrol treated, and DMH + curcumin + resveratrol treated. Morphological analyses of tumor nodules confirmed carcinogenesis in rats after 25 weeks of DMH administration. The DMH treatment significantly induced carcinogenesis, as evidenced by high tumor burden in DMH-treated rats compared with controls. Moreover, DMH treatment caused a significant increase in the protein expressions of p53 as well as p53 phosphorylation in the DMH-treated rats. In addition, a significant rise was observed in 14C glucose uptake and 3H-thymidin uptakes in DMH-treated rats. Furthermore, enzyme activities of lactate dehydrogenase and alkaline phosphatase also showed a significant rise. On the contrary, significant decline was noticed in the p53 acetylation at residue 382 of DMH-treated rats. Conversely, combined treatment with curcumin and resveratrol to DMH-treated rats resulted in significant moderation in the tumor burden. In addition, a significant rise in p53 acetylation was at residue 382 of DMH-treated rats after treatment with phytochemicals. Supplementation with phytochemicals significantly modulated other biophysical and biochemical indices to near normal levels. Therefore, we conclude that curcumin and resveratrol significantly modulated p53 post-translational modifications during gastric cancer.

Topics: Acetylation; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Carcinogenesis; Curcumin; Dimethylhydrazines; Drug Combinations; Male; Phosphorylation; Protein Processing, Post-Translational; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Stomach Neoplasms; Tumor Suppressor Protein p53

Bladder smooth muscle cell death accompanied by hyperplasia and hypertrophy, as induced by inflammation, is the primary cause for poor bladder function. There are emerging evidences on the role of chronic inflammation as a factor involved in carcinogenesis and progression. We aim to determine the bladder smooth muscle pathological changes and dysfunction in chronic prostatitis (CP), to investigate whether resveratrol can improve the urinary dysfunction and the role of c-kit/SCF pathway, that has been associated with the smooth muscle carcinogenesis.. Rat model of CP was established via subcutaneous injections of DPT vaccine and subsequently treated with resveratrol. H&E staining was performed to identify the histopathological changes in prostates and bladders. Western blotting and immunohistochemical staining examined the expression level of C-kit, stem cell factor (SCF), Sirt1, apoptosis associated proteins.. the model group exhibited severe diffuse chronic inflammation, characterized by leukocyte infiltration and papillary frond protrusion into the gland cavities, and a notable increase in prostatic epithelial height. Meanwhile, bladder muscle arranged in disorder with fracture, and cells appeared atypia. The activity of C-kit/SCF was up-regulated, the carcinogenesis associated proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation.. activated c-kit/SCF and bladder muscle carcinogenesis were involved in the pathological processes of CP, which was improved after resveratrol treatment via the downregulation of c-kit/SCF by activating Sirt1.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carcinogenesis; Chronic Disease; Disease Progression; Down-Regulation; Male; Muscle, Smooth; Prostatitis; Proto-Oncogene Proteins c-kit; Rats; Resveratrol; Sirtuin 1; Stem Cell Factor; Stilbenes; Urinary Bladder

Resveratrol (Res) is a natural compound with anti-cancer effects. The goal of this study is to evaluate the suppression of Res in melanoma and investigate its relationship with miRNAs during this process. The in vitro and in vivo anti-cancer abilities of Res were evaluated using cellular assays and animal model. Two melanoma cell lines (A375 and MV3) were used for both in vitro assay and in vivo experiments. qRT-PCR and Western blot were used to detect the changes in gene expressions and protein levels. Dual-luciferase reporter assay and bioinformatic tools were used to further confirm the protein binding and activation of targeted genes. In vitro experiments showed Res significantly decreased the expression of miR-221, an oncogenic microRNA, which was confirmed by the overexpression of miR-221 with or without Res treatment. Mechanistically, we showed that the inhibition of miR-221 by Res was achieved by regulating NF-κB (RELA) activity. In the meantime, we also identified that TFG, a tumor suppressor gene, was a target of miR-221. Finally, using in vivo melanoma model, we confirmed the tumor suppressive effects of Res and our in vitro regulatory network. Res displayed a significant anti-tumor effect on melanoma cells both in vitro and in vivo. The cellular mechanism under this effect involves miRNA regulation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinogenesis; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mice; Mice, SCID; MicroRNAs; Proteins; Resveratrol; Signal Transduction; Stilbenes; Transcription Factor RelA; Xenograft Model Antitumor Assays

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

In cancer, tumor associated macrophages (TAMs) play an important role in the cancer progression, evasion of immunity and dissemination of cancer cells. Inhibition of the activation or the M2 polarization of TAMs is an effective therapy for cancer. In the present study, we investigated the ability of resveratrol (RES) to inhibit lung cancer growth using in vitro and in vivo studies, and examined the underlying mechanisms. We demonstrated that M2 polarization of human monocyte derived macrophage (HMDMs) induced by the lung cancer cells conditioned medium was inhibited by RES. Additionally, RES exhibited inhibitory function in lung cancer cells co-cultured with human macrophages. The activity of signal transducer and activator of transcription 3 (STAT3) was significantly decreased by RES. Moreover, in a mouse lung cancer xenograft model, RES significantly inhibited the tumor growth, which was associated with inhibition of cell proliferation and decreased expression of p-STAT3 in tumor tissues. Further, RES inhibits F4/80 positive expressing cells and M2 polarization in the tumors. These results suggest that RES can effectively inhibit lung cancer progression by suppressing the protumor activation of TAMs.

Topics: Animals; Antineoplastic Agents; Carcinogenesis; Cell Differentiation; Cell Growth Processes; Cell Line, Tumor; Culture Media, Conditioned; Cytokines; Humans; Lung Neoplasms; Macrophages; Mice; Resveratrol; STAT3 Transcription Factor; Stilbenes; Th2 Cells; Tumor Escape; Xenograft Model Antitumor Assays

Resveratrol (RES), present in fruits and plants, is a natural compound that has been shown various medicinal properties, including protection of cardiovascular disease and cancer risk. However, the effects of RES on skin cancer have not been investigated. The present work was designed to explore the anticancer potential of RES against chemical-induced skin carcinogenesis in rats.. Skin carcinogenesis were induced in male Wistar rats by a single topical application of 7,12-dimethylbenz(a)anthracene (DMBA) and 2 weeks later, 12-O-tetradecanoylphorbol-13-acetate (TPA) were topically applied thrice a week to promote skin carcinogenesis. RES at a dose of 1 or 2 mg/kg body weight/week were administered to DMBA treated rats. The effects of RES on DMBA-modified cell-cycle arrest, apoptosis and protein expressions were analyzed by flow cytometry, immunohistochemistry and Western blot, respectively.. RES treatment caused a significant reduction of DMBA-induced tumor occurrence, tumor volume and tumor weight, as compared to DMBA control group. Further, RES treatment increases G2/M arrest and apoptosis by modulating cell-cycle and apoptosis regulated genes such as p53, p21, caspase-3, bax, survivin, cyclin-B and cdc-2 when compared with DMBA control group.. Taken together, the anticancer effect of RES is associated with regulation of cell-cycle and apoptosis in skin cancer, thereby attenuating skin cancer growth. Hence, these findings suggest that RES may be a therapeutic agent for skin cancer treatment.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Apoptosis; Carcinogenesis; Cell Cycle Checkpoints; Male; Rats; Rats, Wistar; Resveratrol; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate

Low-dose resveratrol did not have the opposite effect on intestinal adenoma development when given in a standard diet instead of a high-fat diet, although we agree on the need for more information on the interaction of diet-derived compounds such as resveratrol and other lifestyle, metabolic and hormonal factors.

Topics: Adenoma; Animals; Antioxidants; Carcinogenesis; Chemoprevention; Colorectal Neoplasms; Diet, High-Fat; Female; Humans; Male; Mice; Resveratrol; Stilbenes

Preventive measures against oral carcinogenesis are urgently warranted to lower the high morbidity and mortality associated with this malignancy worldwide. Here, we investigated the chemopreventive efficacy of grape seed extract (GSE) and resveratrol (Res) in 4-nitroquinoline-1-oxide (4NQO)-induced tongue tumorigenesis in C57BL/6 mice. Following 8 weeks of 4NQO exposure (100 µg/ml in drinking water), mice were fed with either control AIN-76A diet or diet containing 0.2% GSE (w/w) or 0.25% Res (w/w) for 8 subsequent weeks, while continued on 4NQO. Upon termination of the study at 16 weeks, tongue tissues were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for molecular targets by immunohistochemistry. GSE and Res feeding for 8 weeks, moderately decreased the incidence, but significantly prevented the multiplicity and severity of 4NQO-induced preneoplastic and neoplastic lesions, without any apparent toxicity. In tongue tissues, both 4NQO + GSE and 4NQO + Res treatment correlated with a decreased proliferation (BrdU labeling index) but increased apoptotic death (TUNEL-positive cells) as compared to the 4NQO group. Furthermore, tongue tissues from both the 4NQO + GSE and 4NQO + Res groups showed an increase in activated metabolic regulator phospho-AMPK (Thr172) and decreased autophagy flux marker p62. Together, these findings suggest that GSE and Res could effectively prevent 4NQO-induced oral tumorigenesis through modulating AMPK activation, and thereby, inhibiting proliferation and inducing apoptosis and autophagy, as mechanisms of their efficacy.

Topics: 4-Nitroquinoline-1-oxide; AMP-Activated Protein Kinases; Animals; Anticarcinogenic Agents; Apoptosis; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Female; Grape Seed Extract; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes; Tongue; Tongue Neoplasms

Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Cisplatin (CIS) is one of the most active cytotoxic agents in current use and it has proven efficacy against various human malignancies. However, its clinical usefulness has been restricted by detrimental side effects, including nephrotoxicity and myelosuppression. The aim of the present study was to attempt to decrease the required dose of CIS, in order to minimize its side effects, and increase its capability to arrest, delay or reverse carcinogenesis. In addition, the present study aimed to ameliorate CIS-resistance in CRC cells, using the natural compound resveratrol (RSVL). RSVL (3,4', 5-trihydroxy-trans-stilbene) is a naturally occurring polyphenol present in the roots of white hellebore (Veratrum grandiflorum O. Loes) and extracted from >70 other plant species. RSVL can exert antioxidant and anti-inflammatory activities, and it has been shown to be active in the regulation of numerous cellular events associated with carcinogenesis. The present study evaluated the effects of RSVL on sensitization of both parent and CIS-resistant HCT-116 CRC cells to the action of cisplatin. The CIS was administered at a dose of 5 and 20 µg/ml, and CIS cytotoxicity, apoptosis, cell cycle and cisplatin cellular uptake were examined in the presence and absence of RSVL (15 µg/ml). RSVL treatment showed anti-proliferative effects and enhanced the cytotoxic effects of cis against the growth of both parent and CIS-resistant HCT-116 CRC cells, with a half maximal inhibitory concentration of 4.20 µg/ml and 4.72 µg/ml respectively. RSVL also induced a significant increase in the early apoptosis fraction and enhanced the subsequent apoptotic effects of CIS. The cellular uptake of CIS was significantly increased in the presence of RSVL, as compared with CIS treatment alone, and RSVL treatment sensitized the CIS-resistant HCT-116 cells. In conclusion, RSVL treatment increased the cytotoxic activity of CIS against the growth of both parent and CIS-resistant HCT-116 CRC cells.

Topics: Antioxidants; Apoptosis; Carcinogenesis; Cell Cycle; Cisplatin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; HCT116 Cells; Humans; Resveratrol; Stilbenes

In this study, the effects of combining ursolic acid + resveratrol, for possible combined inhibitory effects on skin tumor promotion, were evaluated. Ursolic acid, resveratrol, and the combination of ursolic acid + resveratrol were applied topically prior to 12-O-tetracanoylphorbol-13-acetate (TPA) treatment on mouse skin to examine their effect on TPA-induced signaling pathways, epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion. The combination of ursolic acid + resveratrol produced a greater inhibition of TPA-induced epidermal hyperproliferation. The combination of ursolic acid + resveratrol inhibited TPA-induced signaling pathways, including EGFR, STAT3, Src, Akt, Cox-2, Fas, NF-κB, p38 MAPK, c-Jun, and JNK1/2 while increasing levels of tumor suppressors, such as p21 and PDCD4, to a greater extent compared with the groups treated with the individual compounds. Ursolic acid + resveratrol also induced a dramatic increase of p-AMPK-α(Thr172). Combined treatment with ursolic acid + resveratrol resulted in a greater inhibition of expression of proinflammatory cytokines, including Il1a, Il1b, and Il22. Furthermore, NF-κB, Egr-1, and AP-1 DNA binding activities after TPA treatment were dramatically decreased by the combination of ursolic acid + resveratrol. Treatment with ursolic acid + resveratrol during skin tumor promotion with TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the greater ability of the combination of ursolic acid + resveratrol to inhibit skin tumor promotion was due to the greater inhibitory effects on growth factor and inflammatory signaling, skin inflammation, and epidermal hyperproliferation induced by TPA treatment.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Cell Nucleus; Cell Proliferation; Cytosol; Female; Inflammation; Male; Mice; Mice, Inbred ICR; Protein Binding; Resveratrol; Signal Transduction; Skin; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate; Triterpenes; Ursolic Acid

Despite progress in clinical cancer medicine in multiple fields, the prognosis of pancreatic cancer has remained dismal. Recently, chemopreventive strategies using phytochemicals have gained considerable attention as an alternative in the management of cancer. The present study aimed to evaluate the chemopreventive effects of resveratrol (RV) and apocynin (AC) in N-Nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamster. RV- and AC-treated hamsters showed significant reduction in the incidence of pancreatic cancer with a decrease in Ki-67 labeling index in dysplastic lesions. RV and AC suppressed cell proliferation of human and hamster pancreatic cancer cells by inhibiting the G1 phase of the cell cycle with cyclin D1 downregulation and inactivation of AKT-GSK3β and ERK1/2 signaling. Further, decreased levels of GSK3β(Ser9) and ERK1/2 phosphorylation and cyclin D1 expression in the nuclear fraction were observed in cells treated with RV or AC. Nuclear expression of phosphorylated GSK3β(Ser9) was also decreased in dysplastic lesions and adenocarcinomas of hamsters treated with RV or AC in vivo. These results suggest that RV and AC reduce phosphorylated GSK3β(Ser9) and ERK1/2 in the nucleus, resulting in inhibition of the AKT-GSK3β and ERK1/2 signaling pathways and cell cycle arrest in vitro and in vivo. Taken together, the present study indicates that RV and AC have potential as chemopreventive agents for pancreatic cancer.

Topics: Acetophenones; Adenocarcinoma; Animals; Anticarcinogenic Agents; Antioxidants; Blotting, Western; Carcinogenesis; Cell Line, Tumor; Cell Nucleus; Cell Survival; Chemoprevention; Cricetinae; Disease Models, Animal; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Immunohistochemistry; MAP Kinase Signaling System; Mesocricetus; Pancreatic Neoplasms; Phosphorylation; Resveratrol; Stilbenes

It has been reported that methylated analog of resveratrol, 3,4,5,4'-trans-tetramethoxystilbene (DMU-212), demonstrates strong antiproliferative, and proapoptotic activity. The aim of this study was to evaluate the effect of DMU-212 on the activation of nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and signal transducer and activator of transcription 3 (STAT3) transcription factors, using a two-stage model of rat hepatocarcinogenesis (HCC) in Wistar rats. Initiation was performed by a single intraperitoneal injection of N-nitrosodiethylamine (NDEA) (200 mg/kg) followed by promotion with phenobarbital (PB) (0.05%) in drinking water. DMU-212 was administered by gavage in a dose of 20 or 50 mg/kg b.w. two times a week for 16 weeks. There was a significant increase in the activation of all investigated hepatic transcription factors in the NDEA/PB-induced rats. The activation of NF-κB induced by NDEA/PB treatment was suppressed by DMU-212 as evidenced by a reduction of p65 and p50 subunits translocation, DNA binding capacity, increased retention of IκB, and the reduced IKK activity. Moreover, DMU-212 reduced the level of iNOS protein induced by NDEA/PB. Treatment with DMU-212 alone increased the constitutive AP-1 subunits c-Jun and c-Fos levels and c-Jun binding to TRE consensus site. The combined treatment diminished c-Fos level and DNA binding. At a dose of 50 mg/kg, DMU-212 decreased also the STAT3 activation induced by NDEA/PB. These data indicate that DMU-212 may suppress pro-inflammatory transcription factors, particularly NF-κB, and in consequence iNOS expression in rat model of HCC which makes DMU-212 a good candidate for the development of HCC chemopreventive agent.

Topics: Animals; Carcinogenesis; Cyclooxygenase 2; I-kappa B Proteins; Liver; Liver Neoplasms; Male; NF-kappa B; Nitric Oxide Synthase Type II; Rats, Wistar; STAT3 Transcription Factor; Stilbenes; Transcription Factor AP-1

The combination approach is the future of the war against cancer and the present study evaluated molecular mechanics behind the synergistic effects of curcumin and resveratrol during lung carcinogenesis.. The mice were segregated into five groups which included normal control, Benzo[a]pyrene[BP] treated, BP+curcumin treated, BP+resveratrol treated and BP+curcumin+resveratrol treated.. The morphological analyses of tumor nodules confirmed lung carcinogenesis in mice after 22 weeks of single intra-peritoneal[i.p] injection of BP at a dose of 100 mg/Kg body weight. The BP treatment resulted in a significant increase in the protein expressions of p53 in the BP treated mice. Also, a significant increase in the protein expression of phosphorylated p53[ser15] confirmed p53 hyper-phosphorylation in BP treated mice. On the other hand, enzyme activities of caspase 3 and caspase 9 were noticed to be significantly decreased following BP treatment. Further, radiorespirometric studies showed a significant increase in the 14C-glucose turnover as well as 14C-glucose uptake in the lung slices of BP treated mice. Moreover, a significant rise in the cell proliferation was confirmed indirectly by enhanced uptake of 3H-thymidine in the lung slices of BP treated mice. Interestingly, combined treatment of curcumin and resveratrol to BP treated animals resulted in a significant decrease in p53 hyper-phosphorylation, 14C glucose uptakes/turnover and 3H-thymidine uptake in the BP treated mice. However, the enzyme activities of caspase 3 and caspase 9 showed a significant increase upon treatment with curcumin and resveratrol.. The study, therefore, concludes that molecular mechanics behind chemo-preventive synergism involved modulation of p53 hyper-phosphorylation, regulation of caspases and cellular metabolism enzymes.

Topics: Analysis of Variance; Animals; Benzo(a)pyrene; Blotting, Western; Carbon Radioisotopes; Carcinogenesis; Curcumin; Drug Synergism; Immunohistochemistry; Lung Neoplasms; Mice; Phosphorylation; Resveratrol; Stilbenes; Tumor Suppressor Protein p53

The pleiotropic effects of resveratrol include anti-inflammatory, antioxidant, and anticancer activities, and thus unique possibilities exist to explore mechanistic pathways of chemoprevention. The aim of this study was to investigate the role of microRNA (miRNA) alterations induced by resveratrol in the context of chemopreventive mechanisms against dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis in the Apc(Min/+) mouse. To that end, Apc(Min/+) mice were exposed to 2% DSS to enhance intestinal inflammation and polyp development. Concurrently, mice received either vehicle or resveratrol treatment via oral gavage for 5 weeks. Interestingly, treatment of DSS-exposed mice with resveratrol resulted in decreased number and size of polyps, fewer histologic signs of cell damage, and decreased proliferating epithelial cells in intestinal mucosa compared with vehicle. Resveratrol treatment dramatically reversed the effects of DSS on the numbers of specific inflammatory CD4(+) T cells, CD8(+) T cells, B cells, natural killer T cells, and myeloid-derived suppressor cells in mesenteric lymph nodes. Resveratrol treatment also decreased interleukin-6 (IL-6) and tumor necrosis factor-α protein levels and reduced IL-6 and cyclooxygenase-2 mRNA expression. Microarray analysis revealed 104 miRNAs exhibiting >1.5-fold differences in expression in the intestinal tissue of resveratrol-treated mice. Among them, two miRNAs with anti-inflammatory properties, miRNA-101b and miRNA-455, were validated to be upregulated with resveratrol treatment by reverse-transcription polymerase chain reaction. Pathway analysis revealed that numerous differentially regulated miRNAs targeted mRNAs associated with inflammatory processes with known roles in intestinal tumorigenesis. These results suggest that resveratrol mediates anti-inflammatory properties and suppresses intestinal tumorigenesis through miRNA modulation.

Topics: Animals; Carcinogenesis; Cell Proliferation; Colitis; Colon; Colonic Polyps; Cyclooxygenase 2; Dextran Sulfate; Epithelial Cells; Female; Gene Expression Regulation; Interleukin-6; Intestinal Polyps; Lymphocytes; Male; Mice; Mice, Mutant Strains; MicroRNAs; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Tumor-associated macrophages (TAMs) have been shown to promote metastasis and malignancy. Pterostilbene, a natural stilbene isolated from blueberries, has been suggested for anti-cancer effects. Here, we explored the potential cancer stem cells (CSCs)/TAM modulating effects of pterostilbene in breast cancer.. Using flowcytometric and Boyden chamber assay, we showed MCF7 and MDA-MB-231 cells cocultured with M2 TAMs exhibited increased percentage of CD44(+) /CD24(-) CSC population and migratory/invasive abilities. RT-PCR results showed that CD44(+) /CD24(-) cells expressed an increased level of HIF-1α, β-catenin, Twist1, and NF-κB and enhanced tumor sphere forming ability. Additionally, pterostilbene treatment dose dependently overcame M2 TAM-induced enrichment of CSCs and metastatic potential of breast cancer cells. Mechanistically, pterostilbene suppressed NFκB, Twist1, vimentin, and increased E-cadherin expression. Using siRNA technique, we demonstrated that pterostilbene-mediated NFκB downregulation was correlated to an increased amount of microRNA 448. Finally, pterostilbene-mediated suppression in tumorigenesis and metastasis was validated by noninvasive bioluminescence in mice bearing M2 TAM cocultured MDA-MB-231 tumor.. Pterostilbene effectively suppresses the generation of CSCs and metastatic potential under the influence of M2 TAMs via modulating EMT associated signaling pathways, specifically NF-κB/miR488 circuit. Thus, pterostilbene could be an ideal anti-CSC agent in clinical settings.

Topics: Animals; Antigens, CD; beta Catenin; Blueberry Plants; Breast Neoplasms; Cadherins; Carcinogenesis; Cell Line, Tumor; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Gene Silencing; Humans; Hyaluronan Receptors; Hypoxia-Inducible Factor 1, alpha Subunit; MCF-7 Cells; Mice; Mice, SCID; MicroRNAs; Neoplastic Stem Cells; NF-kappa B; Nuclear Proteins; Stilbenes; Tumor Microenvironment; Twist-Related Protein 1; Vimentin

The purpose of our study was to determine the effect of the combined action of phytochemicals on the early stages of skin tumorigenesis, i.e. initiation and promotion. We tested calcium D-glucarate (CG) given in the diet, while resveratrol (RES) and ursolic acid (UA) were applied topically. The 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted multistage skin carcinogenesis model in SENCAR mice was used. Mice received one topical dose of DMBA, then after one month, two weekly doses of TPA for 14 weeks until sacrifice. RES or UA were applied 20 min prior to DMBA or TPA treatment and 2% dietary CG was given from 2 weeks prior to 2 weeks after the DMBA dose or continually beginning 2 weeks prior to the first dose of TPA. UA applied alone and in combination with CG during the promotion stage was the only inhibitor of tumor multiplicity and tumor incidence. A number of combinations reduced epidermal proliferation, but only UA and the combination UA+CG applied during promotion significantly reduced epidermal hyperplasia. DMBA/TPA application resulted in significant increases in c-jun and p50, which were reversed by a number of different treatments. DMBA/TPA treatment also strongly increased mRNA levels of inflammation markers COX-2 and IL-6. All anti-promotion treatments caused a marked decrease in COX-2 and IL-6 expression compared to the DMBA/TPA control. These results show that UA is a potent inhibitor of skin tumor promotion and inflammatory signaling and it may be useful in the prevention of skin cancer and other epithelial cancers in humans.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Cell Proliferation; Cyclooxygenase 2; Female; Gene Expression Regulation, Neoplastic; Glucaric Acid; Humans; Interleukin-6; Mice; Mice, Inbred SENCAR; Phytochemicals; Resveratrol; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate; Triterpenes; Ursolic Acid

3,3',4,4',5,5'-Hexahydroxy-trans-stilbene (M8) is a synthetic resveratrol derivative, advertised as a candidate drug highly effective against numerous malignancies. Because multiple tumors prone to M8 frequently metastasize into the peritoneal cavity, this study was aimed at establishing the effect of M8 on the growth and senescence of human peritoneal mesothelial cells (HPMCs), the largest cell population within the peritoneum, actively involved in the intraperitoneal spread of cancer. The study showed that M8, used at the highest non-toxic dose of 10 μM, impairs proliferation and accelerates senescence in cultured HPMCs via an oxidative stress-dependent mechanism. At the same time, soluble factors released to the environment by HPMCs that senesced prematurely in response to M8 promoted growth of colorectal and pancreatic carcinomas in vitro. These findings indicate that M8 may indirectly-through the modification of normal (mesothelial) cells phenotype-facilitate an expansion of cancer cells, which challenges the postulated value of this stilbene in chemotherapy.

Topics: Carcinogenesis; Cell Line, Tumor; Cellular Senescence; Epithelium; Gastrointestinal Neoplasms; Humans; Oxidative Stress; Peritoneal Neoplasms; Peritoneum; Pyrogallol; Resveratrol; Stilbenes

Topics: Carcinogenesis; Carcinogens; Hydroxylamines; Hydroxylation; Liver; Metabolism; Neoplasms; Pharmacology; Rats; Research; Stilbenes; Urine

Topics: Amides; Animals; Carcinogenesis; Carcinogens; Carcinoma 256, Walker; Hydroxamic Acids; Metabolism; Neoplasms; Rats; Research; Stilbenes; Urine

Topics: Animals; Carcinogenesis; Carcinogens; Liver Neoplasms; Methylcholanthrene; Neoplasms; Neoplasms, Experimental; p-Dimethylaminoazobenzene; Paintings; Rats; Stilbenes

Topics: Animals; Arachidonic Acid; Carcinogenesis; Ear, External; Fatty Acids; Neoplasms; Neoplasms, Experimental; Rats; Stilbenes