[Rich66]

With Taxol only in ER+??

Eur J Cancer. 2010 Mar 9. [Epub ahead of print]
Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells invitro and in vivo.

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Fukui M, Yamabe N, Zhu BT.
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
It was reported recently that resveratrol could sensitise a number of cancer cell lines to the anticancer actions of several other cancer drugs, including paclitaxel. In the present study, we further investigated whether resveratrol could sensitise human breast cancer cells to paclitaxel-induced cell death. Unexpectedly, we found that resveratrol strongly diminished the susceptibility of MDA-MB-435s, MDA-MB-231 and SKBR-3 cells to paclitaxel-induced cell death in culture, although this effect was not observed in MCF-7 cells. Using MDA-MB-435s cells as a representative model, a similar observation was made in athymic nude mice. Mechanistically, the modulating effect of resveratrol was partially attributable to its inhibition of paclitaxel-induced G(2)/M cell cycle arrest, together with an accumulation of cells in the S-phase. In addition, resveratrol could suppress paclitaxel-induced accumulation of reactive oxygen species (ROS) and subsequently the inactivation of anti-apoptotic Bcl-2 family proteins. These observations suggest that the strategy of concomitant use of resveratrol with paclitaxel is detrimental in certain types of human cancers. Given the widespread use of resveratrol among cancer patients, this study calls for more preclinical and clinical testing of the potential benefits and harms of using resveratrol as a dietary adjuvant in cancer patients. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20223651 [PubMed - as supplied by publisher]



Mol Nutr Food Res. 2010 Jun 2. [Epub ahead of print]
Resveratrol confers resistance against taxol via induction of cell cycle arrest in human cancer cell lines.

Mao QQ, Bai Y, Lin YW, Zheng XY, Qin J, Yang K, Xie LP.
Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P. R. China.
Abstract

Resveratrol, which is highly concentrated in the skin of grapes and is abundant in red wine, has been demonstrated to account for several beneficial properties, including antioxidant, anticoagulant, anti-inflammatory and anticancer effects. Taxol is a microtubule-stabilizing drug that has been extensively used as effective chemotherapeutic agents in the treatment of solid tumors. Here, we investigated whether the combination of the two compounds would yield increased antitumor efficacy in human cancer cells. Unexpectedly, resveratrol effectively prevented tumor cell death induced by taxol in 5637 bladder cancer cells. This pronounced antagonistic function of resveratrol against taxol was associated with changes in multiple signal transduction pathways, but not with tubulin polymerization. Importantly, cell cycle analysis showed that resveratrol prevented the cells from entering into mitosis, the phase in which taxol exerts its action. Furthermore, resveratrol blocked the cytotoxic effects of vinblastine but not cisplatin in 5637 cells. Interestingly, resveratrol pre-treatment followed by taxol resulted in synergistic cytotoxicity. Finally, we extended our studies to various human cancer cell lines. Taken together, our results indicate that resveratrol may have the potential to negate the therapeutic efficacy of taxol and suggest that consumption of resveratrol-related products may be contraindicated during cancer therapy with taxol.

PMID: 20521268 [PubMed - as supplied by publisher]




Contrary earlier study (2-Methoxyestradiol=Resveratrol):

Cancer Res. 2005 Jan 15;65(2):387-93.
Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer.

Han GZ, Liu ZJ, Shimoi K, Zhu BT.
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
2-Methoxyestradiol (2-MeO-E(2)), a well-known nonpolar endogenous metabolite of 17beta-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions in vitro and in vivo at pharmacologic concentrations. We determined in the present study whether 2-MeO-E(2) can enhance the anticancer actions of paclitaxel or vinorelbine (two commonly used microtubule-disrupting agents) in several human breast cancer cell lines, including the estrogen receptor-positive MCF-7 and T-47D cells and the receptor-negative MDA-MB-435s and MDA-MB-231 cells. 2-MeO-E(2) in combination with paclitaxel or vinorelbine exhibited a synergistic anticancer effect in these human breast cancer cells in vitro, and this synergistic effect was more pronounced when each of the drugs was used at relatively low concentrations. Additional experiments using female athymic BALB/c nu/nu mice showed that p.o. administration of 2-MeO-E(2) at 30 mg/kg body weight, once a week for 6 weeks, markedly enhanced the activity of paclitaxel or vinorelbine against the growth of the estrogen receptor-negative MDA-MB-231 human breast cancer xenografts in these animals. By contrast, combination of 2-MeO-E(2) with 5-fluorouracil only had a partial additive effect against the growth of these cell lines in culture, and no synergistic effect was observed. Interestingly, when doxorubicin was used in combination with 2-MeO-E(2), the antiproliferative effect of 2-MeO-E(2) was somewhat antagonized by doxorubicin when it was present at high concentrations. Our results showed that 2-MeO-E(2) at nontoxic or subtoxic doses selectively enhanced the effects of certain microtubule-disrupting agents (such as paclitaxel and vinorelbine) against the growth of the receptor-negative human breast cancer cells in culture and also in athymic nude mice.

PMID: 15695378 [PubMed - indexed for MEDLINE]



Resveratrol enhances the sensitivity of doxorubicin-mediated cell proliferation, invasion, and migration in human breast cancer cell lines
The FASEB Journal, 2010 24:964.10 Hyung Sik KIM, Tae Hyung Kim

The current study was designed to investigate the effects of resveratrol in combination with doxorubicin on human breast cancer cells. Doxorubicin-resistant MCF-7 (MCF-7/ADR) and MDA-MB-231 cells were treated with resveratrol and doxorubicin, alone and in combination. Cell viability, cell cycle, apoptosis, migration and invasion all were assessed. Treatment with 1 µM doxorubicin for 24 hours was found to have no effect on viability of MCF-7/ADR and MDA-MB-231 breast cancer cells. However, the combination of doxorubicin and resveratrol significantly reduced viability of the cells; resveratrol improved the doxorubicin-induced cytotoxicity in both cell lines. Combined treatment with resveratrol and doxorubicin reduced MCF-7/ADR and MDA-MB-231 cell migration up to 60% and 80%, respectively, compared to doxorubicin treatment alone. Similarly, there was a significant reduction in the number of invaded cells in assay using Matrigel-coated chambers. To determine the pathway of these anti-invasive effects, the expression levels of genes involved in migration and invasion were examined in both cell lines. MMP-2, MMP-9 and plasminogen activator (u-PA) expression levels were found to be significantly reduced following combination treatment. In addition, the expression levels of TIMPs and RECK were greatly increased as a result of combination resveratrol plus doxorubicin treatment in both cell lines. The authors conclude that resveratrol might be used as a synergistic agent in the treatment of doxorubicin-resistant breast cancer.




NOTE: Study below used MDA-MB-435 cell line..now thought to be derived from melanoma, not breast cancer.

Mol Carcinog. 2010 Jun 22. [Epub ahead of print]
Growth-stimulatory effect of resveratrol in human cancer cells.

Fukui M, Yamabe N, Kang KS, Zhu BT.
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS.



Abstract

Earlier studies have shown that resveratrol could induce death in several human cancer cell lines in culture. Here we report our observation that resveratrol can also promote the growth of certain human cancer cells when they are grown either in culture or in athymic nude mice as xenografts. At relatively low concentrations ( Analysis of cell signaling molecules showed that resveratrol induced the activation of JNK, p38, Akt, and NF-kappaB signaling pathways in these cells. Further analysis using pharmacological inhibitors showed that only the NF-kappaB inhibitor (BAY11-7082) abrogated the growth-stimulatory effect of resveratrol in cultured cells. In athymic nude mice, resveratrol at 16.5 mg/kg body weight enhanced the growth of MDA-MB-435s xenografts compared to the control group, while resveratrol at the 33 mg/kg body weight dose did not have a similar effect. Additional analyses confirmed that resveratrol stimulated cancer cell growth in vivo through activation of the NF-kappaB signaling pathway. Taken together, these observations suggest that resveratrol at low concentrations could stimulate the growth of certain types of human cancer cells in vivo. This cell type-specific mitogenic effect of resveratrol may also partly contribute to the procarcinogenic effect of alcohol consumption (rich in resveratrol) in the development of certain human cancers. (c) 2010 Wiley-Liss, Inc.

PMID: 20572158 [PubMed - as supplied by publisher]









Company based on Resveratrol, Resverlogix with TGF beta targeted anticancer development:

Cancer is a disease characterized by uncontrolled growth and proliferation of abnormal cells. It is now known that certain cancers evade the immune system by secreting TGF-β into the extracellular matrix to hide their presence from the cancer killing immune cells. Thus making TGF- β an attractive therapeutic target to treat the disease. Our scientists are investigating the ability of a naturally occurring protein to inhibit the detrimental effects of TGF-β on the immune system.

Mol Cancer Ther. 2005 Oct;4(10):1465-74.
Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells.

Zhang Q, Tang X, Lu QY, Zhang ZF, Brown J, Le AD.
Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry, Los Angeles 90033, USA.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. In this study, we investigated the effect of resveratrol, a natural product commonly found in grapes and various other fruits, on hypoxia-induced HIF-1alpha protein accumulation and vascular endothelial growth factor (VEGF) expression in human tongue squamous cell carcinomas and hepatoma cells. Our results showed that resveratrol significantly inhibited both basal level and hypoxia-induced HIF-1alpha protein accumulation in cancer cells, but did not affect HIF-1alpha mRNA levels. Pretreatment of cells with resveratrol significantly reduced hypoxia-induced VEGF promoter activities and VEGF expression at both mRNA and protein levels. The mechanism of resveratrol inhibition of hypoxia-induced HIF-1alpha accumulation seems to involve a gradually shortened half-life of HIF-1alpha protein caused by an enhanced protein degradation through the 26S proteasome system. In addition, resveratrol remarkably inhibited hypoxia-mediated activation of extracellular signal-regulated kinase 1/2 and Akt, leading to a marked decrease in hypoxia-induced HIF-1alpha protein accumulation and VEGF transcriptional activation. Functionally, we observed that resveratrol also significantly inhibited the hypoxia-stimulated invasiveness of cancer cells. These data suggested that HIF-1alpha/VEGF could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human cancers.

PMID: 16227395 [PubMed - indexed for MEDLINE]






Suppression of angiogenesis, tumor growth,and wound healing by resveratrol, a natural compound in red wine and grapes
The FASEB Journal express article 10.1096/fj.01-0028fje. Published online June 8, 2001.
Ebba Bråkenhielm,* Renhai Cao,* and Yihai Cao
The first two authors contributed equally to this work.
Corresponding author: Yihai Cao, M.D., Ph.D., Laboratory of Angiogenesis Research,
Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden. Email:
yihai.cao@mtc.ki.se

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ABSTRACT
Resveratrol (3,5,4'-trihydroxystilbene) is a natural compound found in several plants, including grapes, peanuts, and pines, and in their related products. Red wine is probably the most frequently consumed drink that is enriched in resveratrol. We investigated whether drinking resveratrol could suppress angiogenesis, a process of blood vessel growth involved in initiation, development, and progression of many diseases, including cancer, metastasis, and diabetic retinopathy. We found that resveratrol suppresses the growth of new blood vessels in animals.
It directly inhibits capillary endothelial cell growth. It blocks both VEGF- and FGF-receptor mediated angiogenic responses. In addition, resveratrol inhibits the phosphorylation of mitogenactivated kinase isoforms (MAPKp44/MAPKp42) induced by fibroblast growth factor-2 in proliferating endothelial cells in a dose-dependent manner. Oral administration of resveratrol significantly inhibits the growth of a murine fibrosarcoma in mice, and it significantly delays angiogenesis-dependent wound healing in mice. Our findings suggest that ingestion of resveratrol-enriched food could be beneficial for the prevention of cancer. However, its antiangiogenic effect could delay wound healing and possibly other angiogenesis-dependent processes under physiological conditions.

At a concentration of 1 μM, resveratrol significantly inhibited the VEGF-induced
PAE/VEGFR-2 endothelial cell migration (Fig. 1F). These data demonstrate that resveratrol
inhibits both FGF- and VEGF-receptor-mediated endothelial cell growth and chemotaxis.

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To further investigate whether resveratrol could suppress angiogenesis in mammals, we prepared a drinking solution for mice, containing 0.4 μg/ml resveratrol in 1% ethano,l which was equivalent to the amount of resveratrol found in approximately three glasses of red wine

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Our present study is consistent with previous reports that resveratrol inhibits both tumor formation and the growth of tumor implants in animals (8). The growth of primary tumors and metastases depends on the degree of tumor neovascularization (9–11). This study provides compelling evidence that suppression of angiogenesis could be at least one of the mechanisms of the antitumor effect of resveratrol. Consumption of resveratrol could be beneficial in the prevention of angiogenesis-dependent diseases. However, we should emphasize that the antiangiogenic effect of resveratrol could be harmful in situations such as wound healing.
Recent studies suggest that antiangiogenic therapy has to be delivered for long-term periods in order to arrest a tumor at its dormant stage (9, 19). In clinical settings, most angiogenesis inhibitors have to be delivered to cancer patients by systemic injections for several years. Thus, there would be great advantages if oral angiogenesis inhibitors were available. Resveratrol, as a small molecule and an oral angiogenesis inhibitor found in natural food products, could well fulfill the criteria of long-term antiangiogenic therapy without injections.

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Recent studies suggest that antiangiogenesis therapy in combination with other existing
therapies, including chemotherapy and radiotherapy, produces synergistic efficacy against
disease conditions (23). For example, angiostatin and ionizing radiation synergistically suppress tumor growth in animals.

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Taken together with our other recent finding that EGCG in green tea is an angiogenesis inhibitor (4), consumption of various plant products containing polyphenol-based compounds and adequate amounts of red wine may be beneficial in the prevention of cancer. Paradoxically, they might delay physiological processes in which angiogenesis is required.

Gynecol Oncol. 2007 Dec;107(3):450-7. Epub 2007 Sep 10.
Resveratrol inhibits glucose metabolism in human ovarian cancer cells.

Kueck A, Opipari AW Jr, Griffith KA, Tan L, Choi M, Huang J, Wahl H, Liu JR.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, L4000 Women's Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
OBJECTIVES: Resveratrol is a phytoalexin found in grapes that inhibits the in vitro growth of multiple tumor cell types. We showed previously that resveratrol induces autophagic cell death in ovarian cancer cells. Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that autophagy would also be triggered when ovarian cancer cells are nutrient deprived and that resveratrol could in fact be acting by inducing a starvation-like signaling response. METHODS: Ovarian cancer cells were incubated with normal media, media containing resveratrol, glucose free media, or media lacking amino acids. Growth inhibition was determined using the sulforhodamine assay. Cells were evaluated for autophagocytosis by analyzing cleavage of LC3. Glucose uptake, lactate production, and activation of glycolytic regulators pAkt and pmTOR were analyzed following resveratrol treatment. RESULTS: We show here that epithelial ovarian cancer cells are highly sensitive to glucose-deprivation-induced cell death and like resveratrol, glucose deprivation induces caspase-independent cell death with hallmarks of autophagy. Consistent with the hypothesis that resveratrol treatment results in biochemical conditions that mirror a nutrient deprived state, we found that resveratrol dramatically reduces glucose uptake and lactate production. Moreover, resveratrol reduces the levels of phosphorylated Akt and mTOR, two signals that increase glucose uptake and the rate limiting steps in glycolysis. CONCLUSIONS: Our findings are consistent with the hypothesis that resveratrol-induced changes in glucose utilization comprise the mechanism that underlies resveratrol-induced autophagocytosis in ovarian cancer. Inhibition of glycolysis in ovarian cancer with resveratrol or other compounds may be effective therapy for ovarian cancer.

PMID: 17825886 [PubMed - indexed for MEDLINE]





Curr Aging Sci. 2008 Dec;1(3):145-51.
Metabolic effects of resveratrol in mammals--a link between improved insulin action and aging.

Fröjdö S, Durand C, Pirola L.
INSERM, U870, IFR62, Lyon, France.
Resveratrol, a polyphenol found in several vegetal sources, has been shown to possess lifespan-promoting properties in yeast and metazoans, including small mammals. While in yeast and low metazoans resveratrol acts mainly by activating the histone deacetylase Sir2, in mammals it appears to target - besides the Sir2 homolog SIRT1 - several crucial pathways for the control of metabolism, including the AMPK and the insulin-IGF1 receptors axis. The action of resveratrol on these pathways has been linked to its capability to i) prolong lifespan following chronic administration to mice and ii) protect from the development of diet-induced obesity and obesity-dependent metabolic disorders. Here we summarise the current understanding on how resveratrol displays its remarkable properties by acting on the control of insulin secretion and by modulation of insulin action in pheripheral insulin-responsive tissues. Since resveratrol has the potential for pharmacological exploitation to prevent the establishment of insulin-resistance and thus postpone - or even prevent - the onset of type 2 diabetes, toxicologic and pharmacodynamics studies in humans have been initiated. These studies show that resveratrol is non-toxic and easily absorbed by humans. As a drawback, its bioavailability is very limited due to the fast metabolic alterations to which it is subjected in the plasma. Therefore, we also review here the efforts that have been made - in the drug discovery field - to identify new molecules endowed with resveratrol-like pharmacological properties but with better bioavailability, which could prove to possess therapeutic potential.

PMID: 20021385 [PubMed - in process]


Diabetes. 2009 Nov 23. [Epub ahead of print]
AMPK-deficient mice are resistant to the metabolic effects of resveratrol.

Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH.
Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute, National Institutes of Health, 10 Center Dr. Bethesda, MD 20892, USA.
Objective: Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5'-AMP activated kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKalpha1 or alpha2 to determine if the metabolic effects of resveratrol are mediated by AMPK. Research design and methods: Mice deficient in the catalytic subunit of AMPK (alpha1 or alpha2) and wild type mice were fed high-fat diet or high-fat supplemented with resveratrol for 13 weeks. Body weight was recorded by weekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts (mefs) deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro. Results: Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKalpha1-/- mice. In the absence of either AMPKalpha1 or alpha2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD/NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly. Conclusion: We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.

PMID: 19934007 [PubMed - as supplied by publisher]