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Old 03-25-2008, 03:36 PM
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Default Mounting evidence shows red wine antioxidant kills cancer

Rochester researchers showed for the first time that a natural antioxidant found in grape skins and red wine can help destroy pancreatic cancer cells by reaching to the cell's core energy source, or mitochondria, and crippling its function. The study is published in the March edition of the journal, Advances in Experimental Medicine and Biology.

The study also showed that when the pancreatic cancer cells were doubly assaulted -- pre-treated with the antioxidant, resveratrol, and irradiated -- the combination induced a type of cell death called apoptosis, an important goal of cancer therapy.

The research has many implications for patients, said lead author Paul Okunieff, M.D., chief of Radiation Oncology at the James P. Wilmot Cancer Center at the University of Rochester Medical Center.

Although red wine consumption during chemotherapy or radiation treatment has not been well studied, it is not "contraindicated," Okunieff said. In other words, if a patient already drinks red wine moderately, most physicians would not tell the patient to give it up during treatment. Perhaps a better choice, Okunieff said, would be to drink as much red or purple grape juice as desired.

Yet despite widespread interest in antioxidants, some physicians are concerned antioxidants might end up protecting tumors. Okunieff's study showed there is little evidence to support that fear. In fact, the research suggests resveratrol not only reaches its intended target, injuring the nexus of malignant cells, but at the same time protects normal tissue from the harmful effects of radiation.

"Antioxidant research is very active and very seductive right now," Okunieff said. "The challenge lies in finding the right concentration and how it works inside the cell. In this case, we've discovered an important part of that equation. Resveratrol seems to have a therapeutic gain by making tumor cells more sensitive to radiation and making normal tissue less sensitive."

Resveratrol is known for its ability to protect plants from bacteria and fungi. Purified versions have been described in scientific journals as potential anti-cancer, anti-inflammatory and anti-atherogenic agents, and for their ability to modulate cell growth. Other well-known antioxidants derived from natural sources include caffeine, melatonin, flavonoids, polyphenols, and vitamins C and E.

A flurry of antioxidant studies in recent years has not proven how and why they work at the cellular level. At the suggestion of a young scientist in his lab, Okunieff began studying resveratrol as a tumor sensitizer. That's when they discovered its link to the mitochondria.

The discovery is critical because, like the cell nucleus, the mitochondria contains its own DNA and has the ability to continuously supply the cell with energy when functioning properly. Stopping the energy flow theoretically stops the cancer.

Researchers divided pancreatic cancer cells into two groups: cells treated without resveratrol, or with resveratrol, at a relatively high dose of 50 mg/ml, in combination with ionizing radiation. (The resveratrol concentration in red wine can be as high as 30 mg/ml, the study said, and higher doses are expected to be safe as long as a physician is monitoring.)

They evaluated the mitochondria function of the cells treated with resveratrol, and also measured apoptosis (cell death), the level of reactive oxygen species in the cells, and how the cell membranes responded to the antioxidant.

Laboratory experiments showed that resveratrol:

* Reduced the function of proteins in the pancreatic cancer cell membranes that are responsible for pumping chemotherapy out of the cell, making the cells chemo-sensitive.

* Triggered the production of reactive oxygen species (ROS), which are substances circulating in the human body that have been implicated in a number of diseases: when ROS is increased, cells burn out and die.

* Caused apoptosis, which is likely the result of increased ROS.

* Depolarized the mitochondrial membranes, which indicates a decrease in the cell's potential to function. Radiation alone does not injure the mitochondrial membrane as much.

The team also wanted to investigate why pancreatic cancer cells seem to be particularly resistant to chemotherapy. The pancreas, a gland located deep in the abdomen, produces insulin and regulates sugar, and pumps or channels powerful digestive enzymes into the duodenum. This natural pumping process, however, ends up ridding the needed chemotherapy from cells in the pancreas. But just as reseveratrol interferes with the cancer cells' energy source, it also may decrease the power available to pump chemotherapy out of the cell.

"While additional studies are needed," Okunieff said, "this research indicates that resveratrol has a promising future as part of the treatment for cancer."

In the same journal, Okunieff and his group also reviewed why resveratrol protects normal tissue, and found that antioxidants can be designed to take advantage of certain biochemical properties or cellular targets, making them more effective.

"In the majority of studies, melatonin was shown to inhibit development and/or growth of various experimental animal tumors and some human cell lines in vitro. Many tumors do not respond to drug treatment due to their resistance to undergo apoptosis thereby contributing to the development of cancer." Curr Med Chem. 2012 May 18.

[url]http://www.ncbi.nlm.nih.gov/pubmed/22612707

Antioxidants in Cancer Therapy; Their Actions and Interactions With Oncologic Therapies

[url]http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-2346.pdf

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Old 03-25-2008, 04:45 PM
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Default The abrogating effect of alcohol upon VEGF

The AngioRx™ Microvascular Viability Angiogenesis Assay shows the abrogating effect of alcohol upon VEGF. Polyphenols found in red wine (resveratrol) are thought to have anti-oxidant and anti-cancer properties. Polyphenols are antioxidant compounds found in the skin and seeds of grapes. When wine is made from these grapes, the alcohol produced by the fermentation process dissolves the polyphenols contained in the skin and seeds. Red wine contains more polyphenols than white wine because the making of white wine requires the removal of the skins after the grapes are crushed, making an anti-angiogenic enhancer and potentiator effect of the alcohol in red wine.

The Rochester study shows that when pancreatic cancer cells are doubly assaulted with resveratrol and irradiated, the combination induces apoptosis. Resveratrol seems to be therapeutic by making tumor cells more sensitive to radiation and making normal tissue less sensitive. Resveratrol reduced the function of proteins in the pancreatic cancer cell membraines that are responsible for pumping chemotherapy out of the cell, making the cells chemo-sensitive.

What alcohol does is to reduce the secretion of VEGF by the tumor cells. It is measured in the assay. It both reduces VEGF and makes Avastin work better, possibly overcoming tumor resistance to Avastin. Wound healing requires neovascularization. Alcoholics have notoriously poor wound healing. In rat systems, relatively low doses of alcohol do impair vascularization in wounds. Alcohol has a membrane effect, basically puts the cell to sleep so that it doesn't think it requires a blood supply. In the presence of Avastin, you have a lethal 1-2 combination which knocks out the new vessels which are dependent on VEGF for survival.
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Old 12-28-2010, 03:57 PM
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Default The alcohol in red wine

Actually, polyphenols found in red wine - such as resveratrol - are thought to have anti-oxidant or anti-cancer properties. Polyphenols are antioxidant compounds found in the skin and seeds of grapes. When wine is made from these grapes, the alcohol produced by the fermentation process dissolves the polyphenols contained in the skin and seeds. Red wine contains more polyphenols than white wine because the making of white wine requires the removal of the skins after the grapes are crushed.

What makes this interesting in cancer is the anti-angiogenic enhancer and potentiator effect of the alcohol in red wine. What it seems to tell us is that alcohol reduces the angiogenic secretions by the tumor cells. If it does that, it could both reduce these secretions and make an anti-angiogenesis drug less resistant to the tumor cells, making it more effective. In the presence of an anti-angiogenesis drug, you can have a lethel 1-2 combination which knocks out the new blood vessels which are dependent for survival of the cancer. Polyphenols extracted from red wine could be converted into a pill that is highly likely to be safe, relatively easy and inexpensive to create, and deliver (instead of one and a half bottles of red wine per day).

Resveratrol is a type of polyphenol called a phytoalexin, a class of compounds produced as part of a plant's defense system against disease. It is produced in the plant in response to an invading fungus, stress, injury, infection or ultraviolet irradiation. Red wine contains high levels of resveratrol, as do grapes, raspberries, peanuts and other plants.

Resveratrol has been shown to reduce tumor incidence in animals by affecting one or more stages of cancer development. It has been shown to inhibit growth of many types of cancer cells in cell culture. Evidence also exists that it can reduce inflammation. It also reduces activation of NF kappa B, a protein produced by the body's immune system when it is under attack. This protein affects cancer cell growth and metastasis. Resveratrol is also an antioxidant.

Many of the new gene-targeted drugs do not target enough genes. Cancer researchers now recognize hundreds if not thousands of genes must be down-regulated to conquer cancer. In one study, for example, at least 74 genes must be controlled in renal cancer alone (Cancer Biol Ther. 2004 Sep;3(9):889-90. Epub 2004 Sep 24). So-called promiscuous gene inhibitors must be found. A targeted drug like Sutent only down-regulates a small number of genes.

Resveratrol favorably switches many genes, and this has been shown in a renal cancer cell line (PMID: 15467424)(BMC Urol. 2004 Jun 22;4:9). It appears that resveratrol can target "all" genes involved in cancer. It is possible that it also chemosensitizes tumor cells, all the genes within the cell (a potentiator of chemotherapy drugs).
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Old 02-05-2012, 02:04 PM
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Default Alcohol as an anti-angiogenic enhancer and potentiator

Very high doses of antioxidant polyphenols found in red wine - such as resveratrol - shut down and prevent cancerous tumors by cutting off the formation of new blood vessels needed for tumor growth. Phenolics contained in red wine possess antioxidant and antimutagenic properties.

Polyphenols are antioxidant compounds found in the skin and seeds of grapes. When wine is made from these grapes, the alcohol produced by the fermentation process dissolves the polyphenols contained in the skin and seeds. Red wine contains more polyphenols than white wine because the making of white wine requires the removal of the skins after the grapes are crushed.

It's the alcohol itself rather than a particular type of drink or pill that GSK can try to concoct that is responsible for the reduction. Resveratrol has been shown to inhibit growth of many types of cancer cells in clinical specimens of human neoplasms and peripheral blood. Extracts of grape (resveratrol) can elicit protective responses, some mediated by the KEAP-1, NRF-2 pathway.

What is remarkable is that if there is resistance to the anit-angiogenesis drug Avastin (in vitro), it is thought that alcohol has a membrane effect, basically putting the cells to sleep so that it doesn't think it requires a blood supply. Avastin, with alcohol (as an anti-angiogenic enhancer and potentiator), the abrogating effect of the alcohol upon VEGF reduces the secretion of VEGF by the tumor cells.

It both reduces VEGF and makes Avastin work better, possibly overcoming tumor resistance to Avastin. In the presence of Avatin, it has a lethal 1-2 combination which knocks out the new vessels which are dependent on VEGF for survival.

The arbitrary distinction between commercial therapeutics and nutritional substances has created an unnecessary barrier between conventional therapists and those who practice complimentary care. A growing cadre of physicians is developing expertise in natural product therapeutics in parallel to their traditional training.

Chinese herbal and Indian ayurvedic medicine instruct physicians in the appropriate use of natural therapies. An explosion of interest in resveratrides, curcuminoids and terpenes are fueling a rebirth of interest in these naturopathic approaches.

Source: Journal of Internal Medicine, Volume 264, Number 3, September 2008 , pp. 275-287(13)
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Old 02-05-2012, 02:05 PM
gdpawel gdpawel is offline
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Default NIH Reveals Probable Mechanism Underlying Resveratrol Activity?

Researchers at the National Institutes of Health and their colleagues have identified how resveratrol, a naturally occurring chemical found in red wine and other plant products, may confer its health benefits.

The authors presented evidence, published in Cell, that resveratrol does not directly activate sirtuin 1, a protein associated with aging, but rather resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), enzymes that help regulate cell energy.

Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimer's disease, heart disease and cancer, according to lead study author Jay H. Chung, M.D., Ph.D., chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood Institute.

However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells. These findings may help settle the debate regarding resveratrol's biochemistry.

Several previous studies suggested that resveratrol's primary target is sirtuin 1. Chung and colleagues suspected otherwise when they found that resveratrol activity required another protein called AMPK. This would not be the case if resveratrol directly interacted with sirtuin 1.

In this study, the researchers methodically traced out the metabolic activity in cells treated with resveratrol and identified PDE4 in the skeletal muscle as the principal target for the health benefits of resveratrol. By inhibiting PDE4, resveratrol triggers a series of events in a cell, one of which indirectly activates sirtuin 1.

To confirm that resveratrol attaches to and inhibits PDE proteins, Chung's group gave mice rolipram, a drug known to inhibit PDE4. Rolipram reproduced all of the biochemical effects and health benefits of resveratrol, such as preventing diet-induced obesity, improving glucose tolerance, and increasing physical endurance.

Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use. He added that the levels of resveratrol found in wine or foods are likely not high enough to produce significant health benefits or problems. Convincing clinical studies in humans have used about 1 gm of resveratrol per day, roughly equal to the amount found in 667 bottles of red wine.

The study results also suggest that inhibitors of PDE4 may offer the benefits of resveratrol without the potential toxicities arising from resveratrol's interactions with other proteins. One PDE4 inhibitor called roflumilast has already been approved by the FDA for the treatment of COPD (chronic obstructive pulmonary disease).

"This result underscores the need for careful, well-controlled studies to illuminate how these natural products operate," said Robert Balaban, Ph.D., director of the NHLBI Division of Intramural Research. "As Dr. Chung's work suggests, the effects of resveratrol seem to be more complicated than originally thought. However, this new insight into the phosphodiesterases might prove an interesting avenue to pursue."

References: 
Dr. Chung's lab at the NHLBI; Cardiovascular Pulmonary Branch of the NHLBI; the University of California, Davis; the University of North Carolina, Chapel Hill; University of Texas Southwestern Medical Center, Dallas; Sun Yat-sen University, Guangzhou, China; University Medical Center, Utrecht, The Netherlands; and Emerald BioStructures, Bainbridge Island, Wash. 
NIH/National Heart, Lung and Blood Institute
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Old 12-05-2012, 03:18 PM
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Default Resveratrol Can Prevent Cancer, Heart Disease And Diabetes

University of Leicester scientists will present groundbreaking new evidence about how a chemical found in red wine can help prevent cancer on Wednesday, December 5, 2012.

Experts from around the world are set to attend Resveratrol 2012, a major conference at the University which will assess the latest advances in the study of resveratrol - a compound found in the skins of red grapes.

The conference will feature new findings based on the last two years of research, which show how the chemical can help prevent cancer, heart disease and diabetes.

The event follows the first international conference on resveratrol, held in 2010 in Denmark, and evidence from more than ten clinical trials held since will be presented and discussed.

Although the potential health benefits of resveratrol have been known for some time, it has not yet been proven that resveratrol can be effective in humans and the best dose to give remains unknown - meaning that its widespread use cannot safely be recommended at the moment.

Researchers at the University of Leicester have been researching the levels of resveratrol which can be beneficial in preventing cancer.

Using laboratory models, they have found that a daily amount of resveratrol equivalent to two glasses of wine can halve the rate of bowel tumors.

Professor Karen Brown, a member of the University's Cancer Biomarkers and Prevention Group and one of the organisers of Resveratrol 2012, said: "This is the second conference that brings together all the world experts in resveratrol. We have got a fantastic line up covering cancer, heart disease, diabetes, neurological diseases and life extension.

"At the University of Leicester, we want to see how resveratrol might work to prevent cancer in humans. Having shown in our lab experiments that it can reduce tumour development we are now concentrating on identifying the mechanisms of how resveratrol works in human cells."

The Leicester researchers now hope to take their findings from the lab to the next stage by carrying out clinical trials to find the optimum level of resveratrol in humans.

Professor Brown added: "A lot of people take resveratrol as a supplement, but at the moment we don't know how it works or on whom it can work until we have more information - we don't even know the best dose you should take. It has been shown that high doses of resveratrol may potentially interfere with other medication. With all the exciting new studies that are being done - especially the clinical trials - I hope we'll have a clearer picture in the next few years."

The conference included more than 65 lectures, presentations and posters by different researchers from all over the world.

As well as offering opportunities for knowledge sharing and networking, the conference will produce a selection of reports with the latest update on global resveratrol research, as well as the next set of recommendations for the coming year's scientific research and the use of resveratrol.

References: University of Leicester. "International Conference Will Show How Resveratrol Can Prevent Cancer, Heart Disease And Diabetes." Medical News Today. MediLexicon, Intl., 5 Dec. 2012.
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Old 10-05-2013, 07:14 PM
gdpawel gdpawel is offline
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Default Red wine resveratrol remains effective against cancer after the body converts it

Red wine chemical resveratrol remains effective against cancer after the body converts it

A chemical found in red wine remains effective at fighting cancer even after the body's metabolism has converted it into other compounds.

This is an important finding in a new paper published in the journal Science Translational Medicine by Cancer Research UK-funded researchers at the University of Leicester's Department of Cancer Studies and Molecular Medicine.

The paper reveals that resveratrol - a compound extracted from the skins of red grapes - is not rendered ineffective once it is metabolised by the body.

This is an important development, as resveratrol is metabolised very quickly - and it had previously been thought that levels of the extracted chemical drop too quickly to make it usable in clinical trials.

The new research shows that the chemical can still be taken into cells after it has been metabolised into resveratrol sulfates.

Enzymes within cells are then able to break it down into resveratrol again - meaning that levels of resveratrol in the cells are higher than was previously thought.

In fact, the results appear to show resveratrol may be more effective once it has been generated from resveratrol sulfate than it is if it has never been metabolised because the concentrations achieved are higher.

The team, led by University of Leicester translational cancer research expert Professor Karen Brown, administered resveratrol sulfate to mice models.

They were subsequently able to detect free resveratrol in plasma and a variety of tissues in the mice.

This is the first direct sign that resveratrol can be formed from resveratrol sulfate in live animals, and the researchers think it may help to show how resveratrol is able to have beneficial effects in animals.

The study also showed that resveratrol generated from resveratrol sulfate is able to slow the growth of cancer cells by causing them to digest their own internal constituents and stopping them from dividing.

Professor Karen Brown said: "There is a lot of strong evidence from laboratory models that resveratrol can do a whole host of beneficial things - from protecting against a variety of cancers and heart disease to extending lifespan.

"It has been known for many years that resveratrol is rapidly converted to sulfate and glucuronide metabolites in humans and animals - meaning the plasma concentrations of resveratrol itself quickly become very low after administration.

"It has always been difficult to understand how resveratrol is able to have activity in animal models when the concentrations present are so low, and it has made some people skeptical about whether it might have any effects in humans.

"Researchers have hypothesized for a long time that resveratrol might be regenerated from its major metabolites in whole animals but it has never been proven.

"Our study was the first to show that resveratrol can be regenerated from sulfate metabolites in cells and that this resveratrol can then have biological activity that could be useful in a wide variety of diseases in humans.

"Importantly, we did all our work with clinically achievable concentrations so we are hopeful that our findings will translate to humans.

"Overall, I think our findings are very encouraging for all types of medical research on resveratrol. They help to justify future clinical trials where, previously, it may have been difficult to argue that resveratrol can be useful in humans because of the low detectable concentrations.

"There is considerable commercial interest in developing new forms of resveratrol that can resist or overcome the issue of rapid metabolism. Our results suggest such products may not actually be necessary to deliver biologically active doses of resveratrol to people."

Dr Sarah Williams, Cancer Research UK health information officer, said: "This interesting study supports continued research into resveratrol as a therapeutic molecule, but it's important to note that any benefits from the molecule don't come from drinking red wine. It's well established that drinking any type of alcohol, including red wine, increases the risk of developing cancer."

The study was carried out over eight years, and was funded by the Cancer Research UK and National Institute for Health Research (NIHR) Experimental Cancer Medicine Centre in Leicester, and the US National Cancer Institute.

References:

Sulfate Metabolites Provide an Intracellular Pool for Resveratrol Generation and Induce Autophagy with Senescence

Authors: Ketan R. Patel, Catherine Andreadi, Robert G. Britton, Emma Horner-Glister, Ankur Karmokar, Stewart Sale, Victoria A. Brown, Dean E. Brenner, Rajinder Singh, William P. Steward, Andreas J. Gescher and Karen Brown

Sci Transl Med 2 October 2013: Vol. 5, Issue 205, p. 205ra133 DOI:10.1126/scitranslmed.3005870

Citation: University of Leicester. "Red wine chemical resveratrol remains effective against cancer after the body converts it." Medical News Today. MediLexicon, Intl., 4 Oct. 2013.

[url]http://stm.sciencemag.org/content/5/205/205ra133.abstract?sid=11f5be98-fad6-4de0-b395-d27f901509eb
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