stilbenes and Esophageal-Neoplasms

The vascular disrupting agent combretastatin A4 phosphate (CA4P) causes major regression of animal tumours when given as combination therapy.. Patients with advanced cancer refractory to standard therapy were treated with CA4P as a 10-min infusion, 20 h before carboplatin, paclitaxel, or paclitaxel, followed by carboplatin.. Combretastatin A4 phosphate was escalated from 36 to 54 mg m(-2) with the carboplatin area under the concentration curve (AUC) 4-5, from 27 to 54 mg m(-2) with paclitaxel 135-175 mg m(-2), and from 54 to 72 mg m(-2) with carboplatin AUC 5 and paclitaxel 175 mg m(-2). Grade 3 or 4 neutropenia was seen in 17%, and thrombocytopenia only in 4% of 46 patients. Grade 1-3 hypertension (26% of patients) and grade 1-3 tumour pain (65% of patients) were the most typical non-haematological toxicities. Dose-limiting toxicity of grade 3 hypertension or grade 3 ataxia was seen in two patients at 72 mg m(-2). Responses were seen in 10 of 46 (22%) patients with ovarian, oesophageal, small-cell lung cancer, and melanoma.. The combination of CA4P with carboplatin and paclitaxel was well tolerated in the majority of patients with adequate premedication and had antitumour activity in patients who were heavily pretreated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Carboplatin; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Esophageal Neoplasms; Female; Humans; Infusions, Intravenous; Life Expectancy; Lung Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Paclitaxel; Patient Selection; Stilbenes

Pterostilbene (PTE), a natural dimethylated resveratrol analog from blueberries, is known to have diverse pharmacological activities, including anticancer properties. In this study, we investigated the anticancer activity of PTE against human esophageal cancer cells both in vitro and in vivo and explored the role of endoplasmic reticulum (ER) stress (ERS) signaling in this process.. Cell viability, the apoptotic index, Caspase 3 activity, adhesion, migration, reactive oxygen species (ROS) levels, and glutathione (GSH) levels were detected to explore the effect of PTE on human EC109 esophageal cancer cells. Furthermore, siRNA transfection and a chemical inhibitor were employed to confirm the role of ERS.. PTE treatment dose- and time-dependently decreased the viability of human esophageal cancer EC109 cells. PTE also decreased tumor cell adhesion, migration and intracellular GSH levels while increasing the apoptotic index, Caspase 3 activity and ROS levels, which suggest the strong anticancer activity of PTE. Furthermore, PTE treatment increased the expression of ERS-related molecules (GRP78, ATF6, p-PERK, p-eIF2α and CHOP), upregulated the pro-apoptosis-related protein PUMA and downregulated the anti-apoptosis-related protein Bcl-2 while promoting the translocation of cytochrome c from mitochondria to cytosol and the activation of Caspase 9 and Caspase 12. The downregulation of ERS signaling by CHOP siRNA desensitized esophageal cancer cells to PTE treatment, whereas upregulation of ERS signaling by thapsigargin (THA) had the opposite effect. N-Acetylcysteine (NAC), a ROS scavenger, also desensitized esophageal cancer cells to PTE treatment.. Overall, the results indicate that PTE is a potent anti-cancer pharmaceutical against human esophageal cancer, and the possible mechanism involves the activation of ERS signaling pathways.

Topics: Animals; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Survival; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Esophageal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Mice; Signal Transduction; Stilbenes; Xenograft Model Antitumor Assays

Resveratrol has been examined in several model systems for potential effects against cancer. Adenosine monophosphate-activated protein kinase (AMPK) is reported to suppress proliferation in most eukaryocyte cells. Whether resveratrol via AMPK inhibits proliferation of oesophageal adenocarcinoma cells (OAC) is unknown. The aim of this study was to determine the roles of AMPK in the protective effects of resveratrol in OAC proliferation and to elucidate the underlying mechanisms. Treatment of cultured OAC derived from human subjects or cell lines with resveratrol resulted in decreased cell proliferation. Further, inhibition of AMPK by pharmacological reagent or genetical approach abolished resveratrol-suppressed OAC proliferation, reduced the level of p27Kip1, a cyclin-dependent kinase inhibitor, and increased the levels of S-phase kinase-associated protein 2 (Skp2) of p27Kip1-E3 ubiquitin ligase and 26S proteasome activity reduced by resveratrol. Furthermore, gene silencing of p27Kip1 reversed resveratrol-suppressed OAC proliferation. In conclusion, these findings indicate that resveratrol inhibits Skp2-mediated ubiquitylation and 26S proteasome-dependent degradation of p27Kip1 via AMPK activation to suppress OAC proliferation.

Topics: Adenocarcinoma; AMP-Activated Protein Kinases; Anticarcinogenic Agents; Apoptosis; Blotting, Western; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p57; Esophageal Neoplasms; Humans; Proteasome Endopeptidase Complex; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; S-Phase Kinase-Associated Proteins; Signal Transduction; Stilbenes; Tumor Cells, Cultured; Ubiquitination

Dietary lignans, quercetin and resveratrol have oestrogenic properties, and animal studies suggest that they synergistically decrease cancer risk. A protective effect of lignans on the development of oesophageal cancer in humans has recently been demonstrated, and the present study aimed to test whether these three phytochemicals synergistically decrease the risk of oesophageal cancer. Data from a Swedish nationwide population-based case-control study that recruited 181 cases of oesophageal adenocarcinoma (OAC), 158 cases of oesophageal squamous-cell carcinoma (OSCC), 255 cases of gastro-oesophageal junctional adenocarcinoma (JAC) and 806 controls were analysed. Exposure data were collected through face-to-face interviews and questionnaires. The intake of lignans, quercetin and resveratrol was assessed using a sixty-three-item FFQ. Reduced-rank regression was used to assess a dietary pattern, and a simplified dietary pattern score was categorised into quintiles on the basis of the distribution among the control subjects. Unconditional multivariable logistic regression provided OR with 95% CI, adjusted for all the potential risk factors. A dietary pattern rich in lignans, quercetin and resveratrol was mainly characterised by a high intake of tea, wine, lettuce, mixed vegetables, tomatoes, and whole-grain bread and a low intake of milk. There were dose-dependent associations between simplified dietary pattern scores and all types of oesophageal cancer (all P for trend < 0.05). On comparing the highest quintiles with the lowest, the adjusted OR were found to be 0.24 (95% CI 0.12, 0.49) for OAC, 0.31 (95% CI 0.15, 0.65) for OSCC, and 0.49 (95% CI 0.28, 0.84) for JAC. The results of the present study indicate that a dietary pattern characterised by the intake of lignans, quercetin and resveratrol may play a protective role in the development of oesophageal cancer in the Swedish population.

Topics: Adenocarcinoma; Aged; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Case-Control Studies; Diet; Esophageal Neoplasms; Esophagus; Feeding Behavior; Female; Humans; Lignans; Logistic Models; Male; Middle Aged; Odds Ratio; Plant Extracts; Quercetin; Resveratrol; Stilbenes

The anti-cancer activity of resveratrol in human esophageal squamous cell carcinoma (ESCC) was investigated focusing on the role of autophagy and its effects on apoptotic cell death. We demonstrated that resveratrol inhibits ESCC cell growth in a dose-dependent manner by inducing cell cycle arrest at the sub-G1 phase and resulting in subsequent apoptosis. Mechanistically, resveratrol-induced autophagy in the ESCC cells is AMPK/mTOR pathway independent. Since both pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells, this provided a novel strategy in potentiating the anti-cancer effects of resveratrol and other chemotherapeutic reagents in ESCC cancer treatment.

Topics: Apoptosis; Autophagy; Carcinoma, Squamous Cell; Cell Line, Tumor; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; K562 Cells; Microscopy, Electron, Transmission; Resveratrol; Stilbenes

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a polyphenol found in the skin of the grape and red wine, has been found to have chemopreventitive effects in some carcinogenic models. The effects of resveratrol on the initiation of Barrett's metaplasia and the carcinogenic progression to esophageal adenocarcinoma have not been evaluated. The aim of this study was to evaluate the effects of resveratrol on the transition from reflux esophagitis to Barrett's metaplasia to dysplasia to esophageal adenocarcinoma in an established rat model. Male Sprague-Dawley rats underwent esophagoduodenal anastomosis as per institutional approved protocol. They were then treated twice weekly with intraperitoneal injection of 7 mg/kg of resveratrol or saline. Additional nonoperated rats served as controls. The rats in each group were assigned to 1, 3, or 5-month subgroups. The distal esophagus was preserved for blinded histopathological examination at the time of harvest. Thirty-one animals in the 5-month resveratrol group showed a decreased severity of esophagitis (P<0.0001), incidence of intestinal metaplasia (P = 0.3567), and incidence of carcinoma (P = 0.4590) as compared with both the saline and nonoperated control groups. In conclusion, morphological characteristics consistent with decreased esophagitis and incidences of metaplasia and esophageal adenocarcinoma were seen on histopathology in the resveratrol group. Resveratrol resulted in a small diminution of the carcinogenic effects and progression to metaplasia, and further human studies are designed to explore the potential anticarcinogenic mechanism.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Catalase; Disease Models, Animal; Disease Progression; Esophageal Neoplasms; Esophagus; Glutathione; Immunohistochemistry; In Situ Nick-End Labeling; Male; Metaplasia; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

To investigate the apoptosis in esophageal cancer cells induced by resveratrol, and the relation between this apoptosis and expression of Bcl-2 and Bax.. In in vitro experiments, MTT assay was used to determine the cell growth inhibitory rate. Transmission electron microscope and TUNEL staining method were used to quantitatively and qualitively detect the apoptosis status of esophageal cancer cell line EC-9706 before and after the resveratrol treatment. Immunohistochemical staining was used to detect the expression of apoptosis-regulated gene Bcl-2 and Bax.. Resveratrol inhibited the growth of esophageal cancer cell line EC-9706 in a dose-and time-dependent manner. Resveratrol induced EC-9706 cells to undergo apoptosis with typically apoptotic characteristics, including morphological changes of chromatin condensation, chromatin crescent formation, nucleus fragmentation and apoptotic body formation. TUNEL assay showed that after the treatment of EC-9706 cells with resveratrol (10 mmol/L) for 24 to 96 hours, the AIs were apparently increased with treated time (P<0.05). Immunohistochemical staining showed that after the treatment of EC-9706 cells with resveratrol (10 mmol/L) for 24 to 96 hours, the PRs of Bcl-2 proteins were apparently reduced with treated time (P<0.05) and the PRs of Bax proteins were apparently increased with treated time (P<0.05).. Resveratrol is able to induce the apoptosis in esophageal cancer. This apoptosis may be mediated by down-regulating the apoptosis-regulated gene Bcl-2 and up-regulating the expression of apoptosis-regulated gene bax.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma; Esophageal Neoplasms; Humans; Resveratrol; Stilbenes; Tumor Cells, Cultured

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural product occurring in grapes and various other plants with medicinal properties associated with reduced cardiovascular disease and reduced cancer risk. To evaluate the possibility and potential mechanism(s) of which resveratrol inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis, 96 F344 male rats were divided into 10 groups and resveratrol (1 and 2 mg/kg) was administered orally or intraperitoneally (i.p.). In the groups in which resveratrol was administered at 2 mg/kg (orally, for 16 weeks), 1 and 2 mg/kg (i.p., for 16 weeks) and 1 mg/kg (i.p., for 20 weeks), the number of NMBA-induced esophageal tumors per rat was significantly reduced to 78, 62, 54 and 48, respectively (P < 0.05), and the size of maximum tumors in each group with resveratrol treatment was also significantly smaller than that in NMBA alone group (P < 0.05). Although the pathological examination did not indicate significantly decreased incidence of carcinomas by administering resveratrol, the tendency of carcinogensis suppression was observed (P = 0.177). Semi-quantitative RT-PCR and ELISA analysis demonstrated that following NMBA treatment, the expression of COX-1 mRNA was strongly present in tumor tissues, while weakly present in non-tissues; the expression of COX-2 mRNA was induced in both tumor and non-tumor tissues. The production of prostaglandin E(2) (PGE(2)) increased approximately 6-fold, compared with the normal esophageal mucosa. The higher expression of COX-1, the up-regulated COX-2 expression and the increased levels of PGE(2) synthesis were all significantly decreased by administering resveratrol. Our study suggests that resveratrol suppressed NMBA-induced rat esophageal tumorigenesis by targeting COXs and PGE(2), and therefore may be a promising natural anti-carcinogenesis agent for the prevention and treatment of human esophageal cancer.

Topics: Animals; Carcinogenicity Tests; Cyclooxygenase 1; Cyclooxygenase 2; Dimethylnitrosamine; Dinoprostone; Disease Models, Animal; Esophageal Neoplasms; Isoenzymes; Male; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344; Resveratrol; RNA, Messenger; Stilbenes; Transcription, Genetic