Red wine to overcome tumor resistance?

[gpawelski]

They found that very high doses of antioxidant polyphenols shut down and prevent cancerous tumors by cutting off the formation of new blood vessels needed for tumor growth. Polyphenols are commonly found in red wine.

The next cancer drug might come straight from the grocery store, according to new research published in the November 2007 issue of The FASEB Journal. In the study, French scientists describe how high and low doses of polyphenols have different effects. Most notably, they found that very high doses of antioxidant polyphenols shut down and prevent cancerous tumors by cutting off the formation of new blood vessels needed for tumor growth. Polyphenols are commonly found in red wine, fruits, vegetables, and green tea.

At relatively low doses, the French researchers found that the same polyphenols play a beneficial role for those with diseased hearts and circulatory systems by facilitating blood vessel growth. The amount of polyphenols necessary for this effect was found to be the equivalent of only one glass of red wine per day or simply sticking to a healthy diet of fruits and vegetables containing polyphenols.

http://www.fasebj.org/cgi/content/abstract/21/13/3511

In a recent study published in the British Journal of Cancer, phenolics contained in wine possess antioxidant and antimutagenic properties. However, it says that the alcohol itself rather than a particular type of drink is responsible for the reduction in risk.

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.

http://www.reuters.com/articlePrint?art ... 7420070824

[RandyW]

THanks for posting this Greg

[gpawelski]

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 these two studies 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.

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 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).

[gpawelski]

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.

University of Rochester Medical Center

http://www.urmc.rochester.edu/

[gpawelski]

It is increasingly being realized that circulating microvascular cells may be important markers for a wide variety of cancers. An article appeared in the September issue of Journal of Internal Medicine, "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood," reporting a novel system that was developed for testing anti-microvascular drug effects in fresh biopsy specimens of human tissue, cavitary fluids and blood.

Three-dimensional microclusters of tumor cells were isolated from fresh tumor biopsy specimens and cultured for 96 hours (polypropylene, round-bottomed, 96-well microplates) in the presence and absence of test drugs.

A private laboratory has worked with the use of DMSO and/or alcohol as an anti-angiogenic enhancer and potentiator and has measured it with fresh "live" tumor specimens in cell culture assays.

What alcohol does is to reduce the secretion of VEGF by the tumor cells. The assay shows the abrogating effect of alcohol upon VEGF. It both reduces VEGF and makes a drug like 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.

Alcolol may have a membrane effect, basically puts the cell to sleep so that it doesn't think it requires a blood supply. In the presence of a drug like Avastin, you have a lethel 1-2 combination which knocks out the new vessels which are dependent on VEGF for survival.

For an antiangiogenesis effect, it would be necessary to drink a bottle of wine per day, an amount considered unhealthy. A better option may be polyphenols extracted from plants converted into a tablet. The use of plant polyphenols as therapeutic tools presents important advantages, because they have a good safety profile, a low cost and they can be obtained everywhere on the planet.

Source: J Intern Med 2008; 264: 275-287

[CaroleHammett]

Greg:

I've been taking Resveratrol sporadically in cap form for at least a year, and at one point was also drinking a red glass of wine with dinner every night (a punishment since my dinners are usually fish, which doesn't go with red! )

I am confused now, however, since on one hand it seems that alcohol is the key, yet on the other hand that one should take caps as one would otherwise have to drink too much wine (not necessarily a punishment! )

Affectionately and appreciatively, but nevertheless confused (as always),

Carole

[gpawelski]

Carole. You bring up something very interesting. Somehow I think about the recent vitamin C study. In subsequent studies, it failed to show a benefit, but those studies involved vitamin C given orally. The new study involved injections of vitamin C to enable greater concentrations of it to get into the system.

Is the same type of mechanism happening with regards to alcohol (polyphenols found in red wine) vs. Resveratrol given orally? I don't know? In the study published in the British Journal of Cancer, phenolics contained in wine possess antioxidant and antimutagenic properties. However, it says that the alcohol itself rather than a particular type of drink is responsible for the reduction in risk.

Alcohol in red wine could overcome tumor resistance to Avastin? What the recent Weisenthal study has shown is that what alcohol does is to reduce the secretion of VEGF by the tumor cells. They measured it. It both reduces VEGF and makes Avastin work better, overcoming tumor resistance to Avastin.

His new 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. However, it is the anti-angiogenic enhancer and potentiator effect of the alcohol in red wine. In the presence of Avastin, there is a lethel 1-2 combination which knocks out the new vessels which are dependent on VEGF for survival.

The recent University of Florida study, that I've posted on another thread, found that talc has the ability to stunt cancer growth by cutting the flow of blood to metastatic lung tumors. Their study revealed that talc stimulates health cells to produce 10-fold higher levels of endostatin, a hormone released by healthy lung cells.

Talc causes tumor growth to slow down and actually decreases the tumor bulk. Talc is able to prevent the formation of blood vessels, thereby killing the tumor and choking off its growth. Previous studies had been disappointing with pharma-produced endostatin because most clinicians had injected the hormone directly into patient, where the hormone broke down in the body before it had a chance to slow the spread of cancer.

UF researchers "rethought" the situation by understanding that by allowing talc in the chest cavity, thus constantly causing normal cells to produce endostatin, it inhibits the growth of tumors.

Many time, "whiz bang" research often gets a pass without much thought. The problem is that few scientific discoveries work the way we think and few scientists take the time to think through what it is they have discovered. I'm glad a few do!

As long as there is a predominance of scientific discovery with the mindset of "drug" discovery, instead of scientific discovery, we'll continue to muddle along the path to scientific cure for this disease.

There is something else that is interesting in regards to alcohol. Paclitaxel (taxol), which is given intravenously, is difficult to use. Because it does not dissolve in water, the drug must be mixed in Cremophor, a combination of castor oil and alcohol that can cause severe allergic reactions. To reduce the risk, patients who receive Cremophor first receive a steroid and an antihistamine.

The most common reasons that Taxotere (Docetaxel) can be subsituted for Paclitaxel are related to the increased risk of serious hypersensitivity reactions to Paclitaxel, which is formulated in Cremephor-EL (alcohol and polyoxyethylated castor oil), as well as the risk of neuropathy. Docetaxel has less risk of hypersensitivity reactions and neuropathy, but greater risk of bone marrow suppression.

[CaroleHammett]

Greg.

Thanks for the additional info. I'm still trying to digest it, but in the meantime I've developed a compromise for the alcohol v. Resveratrol caps dilemna: I went out and bought a bottle of red which I use to wash down the caps!

Affectionately and appreciatively,

Carole

[gpawelski]

LOL!!!

[SandraL]

Well I have now seen and read this post many times and finally can not resist the urge to say that I absolutely consider red wine an integral part of my treatment plan! Have a great day

[CaroleHammett]

Sandra:

Be a good girl! The red wine is a no-no unless you use it to wash down the Resveratrol tabs!

With love, affection and Baileys on the rocks,

Mama Carole

PS to all: I am so far behind on the board and with my PMs and emails that I'll never catch up... so just take heart that I'm still around, as evidenced by the fact that I haven't lost my sick sense of humor, and doing well, as evidenced by the fact that I'm still around.

[Caren]

I don't know what to make of this thread actually. I'll also be honest in saying that I haven't read the whole thread.

My dad has been drinking more than a glass of red wine a day for years and years and yet he has a 6-7cm tumour..........

[gpawelski]

What I've presented here is the anti-angiogenic enhancer and potentiator effect of alcohol in red wine (not the red wine itself). It seems that alcohol reduces the angiogenic secretions by the tumor cells. Doing so, it could both reduce these secretions and make an anti-angiogenesis drug (like Avastin) less resistant to tumor cells, making it more effective.

Perhaps I should have separated the red wine research from the alcohol research (which I've done on other boards). The abrogating effect of alcohol upon VEGF. What alcohol and/or DMSO does is to reduce the secretion of VEGF by the tumor cells.

I don't encourage the drinking of alcohol for cancer prevention. Scientists have found effective substances in alcohol, vitamin C, talc, endostatin, herbs, or whatever. But these cannot be patented and have pharmaceutical sponsors for "GoodHouseKeeping Seal of Approval" clinical trials.

[CaroleHammett]

Hi, Greg.

All joking aside, I really have been drinking a single glass of red wine each night to "wash down" my resveratrol caps (based on the positive studies re both a glass of red a day and resveratrol caps plus your data above).

As you know, I'm science-deficient in terms of trying to understand much of what you post until I've read and re-read (and asked you a ton of questions!).

One of the areas I'm still working at trying to understand is angiogenesis. You mention anti-angiogenic drugs such as Avastin being enhanced by alcohol in red wine. Today's question is: Are all anti-angiogenics drugs or are there non-drug anti-angiogenics that might be added to, for example, red wine, and if so, what are they?

Thanks,

Carole

PS Apologies in advance if the above question doesn't make sense! But this time, instead of attributing it to my being science-deficient, let's just blame the red!

[gpawelski]

Based on the positive studies (Eur J Cancer Prev. 2003 Oct;12(5):417-25), I hope it is a robust red wine. The level of resveratrol in modern wines has plummeted.

Again, I don't encourage the drinking of alcohol for cancer prevention. But I had my wife on a regimen of antioxidant supplements, including Alpha Lipoic Acid (the antioxidant's antioxidant).

Private laboratories performing cell-based tests are about the only entities that do "real world" studies, because their studies require fresh, viable specimen, which must be accessioned and tested in "real time," under "real world" conditions.

The recent study that was published in the Journal of Internal Medicine, on the abrogating effect of alcohol upon VEGF, was done with the drug Avastin. The enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each one alone.

Are there other anti-angiogenic drugs? We'll see (Tarceva may be one). The agents of choice in this study were DMSO and/or alcohol + Avastin to measure the effect of microvascular cell death in clinical specimens of human neoplasms.

[Barb73]

Greg,

During Bill's last regimen of Avastin/carboplatin/taxol, I asked the doctor if it would be OK for Bill to ingest a glass or two of red wine. He said that it would be fine.

Here's the thing. I have always had a glass of Cabernet Sauvignon with my supper. Bill has never. But when he decided to partake of the wine, his choice was a Port (sweet). I wonder if that sugar difference (aside from the alcohol itself issue) could be a factor in the equation?

When he has the Port, he has something with some fat in it (to slow the sugar processing). Forgive my lack of scientific knowledge regarding this, but you have prompted me to delve a bit.

Since there is no stupid question when on a "quest" for knowledge, I know you will not consider this silly.

Thanks Greg,

Barbara

[gpawelski]

Absolutely not, Barbara! I love thought provoking questions/statements. Whether the sugar difference could be a factor in the equation depends on the definition of what sugar (glucose) does.

As you may know, many of the new targeted drugs home in on a receptor (EGFR) that is abundant on the surface of cancer cells. By blocking this receptor, it disrupts cellular signals that cause tumor cells to grow and prolifereate.

Some targeted drugs work by preventing an enzyme (tyrosine kinase) from launching a signaling cascade that fuels tumor cell growth. However, the limited response to these treatments (10% to 20%) has caused cancer experts to wonder if EGFR's role in the disease is limited.

Scientists at M.D. Anderson reported recently that they discovered that EGFR plays a second role in promoting the survival of cancer cells. It can help tumor cells get a constant and plentiful supply of the sugar glucose, a critical nutrient.

Cancer cells have a voracious appetite for glucose. Glucose is their unique source of energy, and because of the relatively inefficient way cancer cells burn this fuel, they use up a great deal of it. Because cancer cells require so much glucose, they virtually steal it away from the body's normal cells, thus starving them.

FDG-Pet Scans monitor the biochemical functioning of cells by detecting how they process certain compounds, such as glucose (sugar). Cancer cells metabolize glucose at a much higher level than normal tissues. By detecting increased glucose use with a high degree of sensitivity, PET identifies cancerous cells, even at an early stage.

When using a Pet Scan, a technician will give a cancer patient a solution of radioactive glucose (a radioactive tracer or tagged glucose). Since cancer cells consume 15 times more glucose than normal cells, the cancer cells will absorb 15 times more of this radioactive glucose than normal cells. The result is that when they do the Pet Scan, the cancer cells show up in the x-ray.

Anyway, despite interference from the targeted drugs, EGFR also can help the cancer cells thrive by helping to assure their food supply (glucose).

EGFR does this by binding to and stabilizing another protein on the cell surface called SGLT1 (sodium/glucose co-transporter). Without this mechanism, the cell will undergo glucose starvation (the cell essentially devours itself and dies).

The glucose role is independent and thus unaffected by turning off the kinase-activated growth signals. Even with drugs that block the kinase activity, the tumor cell that expresses very high levels of EGFR and very high levels of SGLT1 will remain viable.

That is why in chemotherapy treatment selection, EGF-targeted drugs are poorly-predicted by measuring the preferred target EGFR. They can, however, be well-predicted by measuring the effect of the drugs on the "function" (the net effect of all processes) of live cells.

[Barb73]

Thank you, Greg.

It seems that in order to encourage apoptosis, we need some agent which affects "all" the factors involved in keeping the cancer cells alive.

It is complicated and will take much thinking and development in labs to solve that nemesis.

I am printing up your explanation in order to read it again. It takes me a while to absorb scientific concepts. I may even need to draw myself a picture.

Science wasn't my major. However, I have become a veracious reader since Bill's diagnosis, and do appreciate your analysis on this subject.

Too bad we can't invent a sugar sponge that selectively removes sugar from the cancer cells, but leaves the "normal" cells their portion.

Thank you again, Greg.

Barbara

[gpawelski]

The short term future of cancer therapeutics is combinations of targeted agents. Today, we have the ability to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then use two, three, four or more targeted therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process.