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  • The Promise Of Resveratrol: Another Step Closer

    August 7, 2009: by ResveratrolNews

    The Chicago Tribune report of a terminal cancer patient’s successful prolonged survival, credited to her use of a drug that inhibits the mTOR-gene pathway combined with “fresh-preserved” grapefruit juice, should have striking impact upon longevity seekers.

    The reason? — The drug used to inhibit the mTOR gene pathway is rapamycin, recently heralded in the news media because it was found to significantly prolong (by 14%) the life of lab animals even though it was employed at a latter stage of their lifespan. [Nature. 2009 Jul 16;460(7253):392-5]

    Rapamycin levels are so enhanced by grapefruit juice that once-weekly dosage produced drug concentrations equal to every-day dosing without juice.

    Molecules in grapefruit juice are known to enhance the effects of drugs by inhibiting detoxification enzymes in the liver.

    Rapamycin is an immunosuppressant drug used to prevent organ rejection in transplant patients.

    Enter another anti-aging molecule – resveratrol, which also inhibits the mTOR gene and is widely available as a dietary supplement. Rapamycin exerts strong mTOR inhibition than resveratrol, but it is believed that concentrations of resveratrol can be achieved to quell cancer. [Cell Cycle 2009 June 8 (12): 1901-04]

    Resveratrol treatment is believed to result in biochemical conditions that mirror a nutrient deprived state. In fact, resveratrol dramatically reduces glucose (sugar) uptake into tumor cells and lactic acid by-production. One way resveratrol inhibits tumor growth is by inhibition of sugar utilization which is a growth factor for tumor cells. [Gynecology Oncology 2007 Dec; 107(3):450-7]

    Copyright 2009 Bill Sardi, Resveratrol News

    chicagotribune.com :

    Grapefruit juice found to give cancer treatment a boost

    Doctors say chemicals in juice prevent enzyme from breaking down certain drugs, boosting their effects

    By Vanessa McMains
    Tribune reporter; August 5, 2009

    When Albina Duggan of Bourbonnais was diagnosed with Stage IV cancer, it had spread from her liver to her spine and lymph nodes.

    “[The doctor] told me I had three years — if lucky, five — to live,” she said. Having endured four surgeries and intensive radiation treatment, Duggan enrolled in clinical trials as a last resort.

    Five years later, the 41-year-old mother of four has defied expectations: Her tumors have shrunk by half and doctors no longer are setting limits on her life expectancy.

    Duggan attributes her new hope to an unusual cancer treatment being tested at the University of Chicago — the drug rapamycin, supplemented by grapefruit juice.

    Unlike most beverages, grapefruit juice contains a chemical that boosts the potency of many drugs in the body. To avoid a dangerously high dose of medication, patients are often advised to not wash down pills with grapefruit juice.

    U. of C. cancer researcher Dr. Ezra Cohen wondered if that quality could be used for good — if drinking the juice could boost the effectiveness of cancer drugs.

    For example, rapamycin and related drugs normally must be taken daily to be effective against cancer. Taking it once a week would lower the cost and decrease adverse side effects, including suppression of the immune system and diarrhea.

    This spring, at the American Association for Cancer Research’s 100th annual meeting in Denver, Cohen presented early results that showed drug levels in patients taking rapamycin once a week and drinking 8 ounces of grapefruit juice every day were similar to the levels expected from taking the drug daily without juice.

    Cohen said about a third of the 25 patients enrolled in the study long enough to be evaluated have seen their tumors stop growing while on the treatment, with Duggan the most dramatic example.

    “Mrs. Duggan amazed everyone in the study,” he said.

    Most of the other participants have cancers of the kidney or prostate that have reacted well to rapamycin in past studies. Duggan’s rare cancer, which involves blood vessels, apparently also is responsive to the drug.

    Rapamycin prevents cells from multiplying, which is important for keeping cancer growth in check. But because an enzyme in the intestine breaks down the drug, only a fraction of the rapamycin a patient swallows gets into the system, Cohen said.

    Grapefruit juice contains chemicals that block this enzyme, which, he said, “normally protects us from other toxic chemicals and metabolizes them to harmless byproducts.” These chemicals, called furanocoumarins, prevent rapamycin from being broken down so the body can absorb more of it.

    However, not just any grapefruit juice will work. The grocery-store grapefruit juice Cohen initially used did not cause an increase in rapamycin levels in the blood. “We were scratching our heads trying to figure out what was wrong,” he said.

    By a stroke of luck, the Florida Department of Citrus saw a report about Cohen’s work on television. The department contacted Cohen and told him the key chemicals in grapefruit juice have a short shelf life and can break down during the time it takes to process and sell the juice.

    The citrus department sent Cohen a more potent juice that had been freshly frozen, which turned out to be effective for raising drug levels in the blood.

    Dr. Brian Rini of the Cleveland Clinic Taussig Cancer Institute cautioned people against thinking of grapefruit juice as an all-purpose booster. Certain medications, such as blood-pressure medicines, can be unsafe when taken with grapefruit juice. “It can elevate drug levels for good or bad.”

    Still, he praised Cohen for helping to find ways to deliver drugs that are cheaper and more convenient for patients.

    Duggan said that when she was enrolled in other clinical trials with different cancer drugs, she experienced sore legs and feet, rashes and hair loss. With this combination, though, she said “side effects are minimal. I feel healthy and full of energy.”

    Duggan said she walks three miles daily.

    “Once a week I take my rapamycin and that is the day that is hardest because I feel fatigued, but I sleep it off,” said Duggan, who has been enrolled in the trial since March 2008.

    The typical monthly cost for rapamycin treatment is $1,000, but taking less frequent doses with grapefruit juice brings down the price to about $250, Cohen said.

    Thrilled with her treatment, Duggan said her life expectancy is “indefinite.”

    “There is nothing in my charts that will point to any number,” she said. “I might outlive everybody.”

    Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.

    Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA.
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA. david.harrison@jax.org

    Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

    At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence.

    Demidenko ZN, Blagosklonny MV.
    Oncotarget, Albany, NY, USA.

    Here we demonstrated that, at cytostatic, near-toxic concentrations, resveratrol inhibited S6 phosphorylation and prevented the senescence morphology in human cells. Using a sensitive functional assay, we found that resveratrol partially prevented loss of the proliferative potential associated with cellular senescence. Resveratrol was less effective than rapamycin, because aging-suppression by resveratrol was limited by its toxicity at high concentrations. We discuss whether concentrations of resveratrol that inhibit mTOR (target of rapamycin) and suppress cellular senescence are clinically achievable and whether partial inhibition of mTOR by resveratrol might be sufficient to affect organismal aging.

    Cell Cycle. 2009 Jun 15; 8(12):1901-4.

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