DNC NEWS: Resveratrol Synergy

Several years ago I wrote about an up and coming plant extract called resveratrol. At the time I had a half dozen recent abstracts suggesting that this plant compound might inhibit cancer cell growth. I updated the article a few years later as more information was published. I took a few moments the other day to see what was new. Research on resveratrol continues to avalanche with most of it focusing on resveratrol's ability to inhibit cancer growth and to cause apoptosis in cancer cells. Apoptosis is a self destruct mechanism programmed into cells which will cause cell death if the cell is injured or mutated. Cancer cells frequently have lost this self destruct mechanism and continue to reproduce despite the detrimental effect this has on the organism in general. Certain plant extracts are able to stimulate or repair this suicide program allowing cancer cells to destroy themselves. Understanding how this happens is obviously of interest to scientists and drug manufacturers. A recent look at PubMed's search engine revealed close to a thousand hits for “resveratrol”, too many for this fellow to read. Narrowing the search down to “resveratrol AND apoptosis” reduced the hits to just under a hundred. Enough to say scientific interest has not waned.

Resveratrol continues to show use against a variety of different cancer types including Pancreatic c[1] , Leukemia [2] [3] [4] , Esophageal [5] , Melanoma [6] , and Prostate cancer [7] [8] .

What is probably one of the most interesting effects of resveratrol is its ability to, “ exert sensitization effects on cancer cells that will result in a synergistic cytotoxic activity when resveratrol is used in combination with cytotoxic drugs in drug-resistant tumor cells.” [9] In simpler words resveratrol acts to counter drug resistance. A frequent problem in treating cancer is that tumors develop an immunity or resistance to the chemotherapy drugs that are being used to attack the cancer cells. Giving resveratrol during treatment can prevent drug resistance from developing as well as having its own inhibitory and apoptosis stimulating effect. The important word though is synergistic, the more than the sum of the parts synergy.

Another study which used the term synergy in referring to resveratrol looked at pancreatic cancer. Researchers at the University of California , Los Angeles examined the effects of several different plant chemicals on the growth rate of pancreatic cancer cells. They tested the effect of quercetin in mice showing that it decreased primary tumor growth, increased apoptosis and prevented metastasis. They followed this study with in vitro study combining quercetin with other plant extracts. Combining quercetin and resveratrol “markedly enhanced apoptosis”. The effect was “greater than the expected additive response.” [10] Again we come to this concept that the effects of plant extracts that are cancer inhibitory have effects greater in combination than simple addition would count for. I have written about this in the past regarding milk thistle and other extracts. How do we account for synergistic action in prescribing therapy? There is no mathematical model that is accurate enough to predict the degree of synergistic action and how to modify doses yet. Boik has made an attempt at doing this but the science is so inexact that I am hesitant to take his numbers too. The important point though is to be aware which compounds may act synergistically and that using these compounds together may give more benefit than using them alone even in larger doses.

Our earlier newsletter:

DNC NEWS # 25: Resveratrol and Cancer Prevention:
Subject:  Resveratrol, a chemical constituent of grapes, has been shown to inhibit growth of several cancer types.

    The grape vines I planted last Spring are growing unbelievably slow: 
We'll move before I ever get to taste their fruit.  In contrast to my slow growing grapes, scientific interest in grapes and their constituents is growing faster than I can keep up with.  The interest was initially fueled by the “French Paradox.”  Though it sounds like a good title for a movie, the French Paradox refers to the fact that the French have a low incidence of heart disease despite a high fat diet that should have increased their
disease rates.  Part of the explanation has been attributed to the large amount of red wine in their diet.  There are a number of protective factors that have been isolated in grapes. One of these chemicals called Resveratrol is about to become a hot item.  Since the beginning of this year Resveratrol has found a new use:  cancer prevention and treatment.
   
    This coming September, Cancer Letters  will  publish a study saying that Resveratrol can slow the growth rate of colon cancer cells by 70%.1 A study published in June stated that , “Resveratrol influences dose dependently the proliferative and apoptotic activity of human tumor and endothelial cells.......Higher doses  (10.0-100.0 microg/ml) induce apoptosis and decrease mitotic activity, ......”2 Another June study showed that breast
cancer cells, especially hormone dependent cell lines, were likewise slowed.3 In May, a study showed a similar dose dependent inhibition of leukemia cells in part by inducing apoptosis.4 Last February AntiCancer Research published a study in which 4 days of treatment with Resveratrol decreased PSA secretion by prostate cancer cells by 80%.5  One unusual use for Resveratrol has been suggested.  It might provide a method of “purging” the bone marrow of cancerous cells during a bone marrow transplant.6
    Another study published in June suggested an explanation of why the French diet has advantages.  The effect of Resveratrol in the body is limited to some degree by a process called sulfation.  How fast Resveratrol is sulfated in the liver and made inactive is hindered by certain chemicals, most notably by the flavonoid quercetin.  High levels of quercetin in the diet increase the action of Resveratrol. 7 The best food sources of
quercetin are onions, wine, and apples, all well represented in the French diet.  Alcohol seems to directly enhance the ability of resveratrol to inhibit cell growth,8 which is an argument in favor of wine over pills.

    Older research (back from the last century, 1999) strongly suggests that
Resveratrol has a role in preventing and treating prostate cancer9, oral
squamous cell carcinoma10, and leukemia.11
    The potential of this substance appears to be at all stages of cancer
prevention and treatment.  It prevents initiation of cancer at its earliest stages with antioxidant and anti mutagenic properties. It is a cyclooxygenase inhibitor and induces phase II liver enzymes responsible for carcinogen detoxification.  It has anti inflammatory effects, inhibiting the production of arachidonic metabolites by cycloxgenases.  It prevents progression by inducing cancer cells to differentiate normally.  It counteracts cancer cell induction by various toxic substances.  It lowers levels of dangerous highly reactive oxygen chemicals and restores glutathione levels12 
Trust me, it doesn't get better than this.
     Though originally isolated from grapes, the best commercial source for Resveratrol is a Chinese herb, Polygonum cuspidatum .  We will begin selling Resveratrol in our office pharmacy.  We have found a product that is an extract of Polygonum cuspidatum   in 200 mg capsules standardized to 20% total resveratrols.  The price is $15.50 for bottles of 60 capsules or $27 for bottles of 120.  At this time the suggested dose is just one capsule per day.
This dose was established based on estimates needed for cardiovascular protection.  The manufacturer was still unaware of this new burst of cancer research when I contacted them and we may see dose changes.

Obviously it's time to learn how to pronounce this word

References from original Newsletter:

1.  Schneider Y, Vincent F, Duranton B, Badolo L, Gosse F, Bergmann C, Seiler N, Raul F.   Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells.  Cancer Lett 2000 Sep 29;158(1):85-91.
2.Szende B, Tyihak E, Kiraly-Veghely Z . Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures.  Exp Mol Med 2000 Jun 30;32(2):88-92. 
3.    Damianaki A, Bakogeorgou E, Kampa M, Notas G, Hatzoglou A,  Panagiotou S, Gemetzi C, Kouroumalis E, Martin PM, Castanas E.  Potent inhibitory action of red wine polyphenols on humanbreast cancer cells.  Cell Biochem 2000 Jun 6;78(3):429-41.
4.   Tsan MF, White JE, Maheshwari JG, Bremner TA, Sacco J . Resveratrol
induces Fas signalling-independent apoptosis inTHP-1 human monocytic
leukaemia cells. Br J Haematol 2000 May;109(2):405-12.  
5.    Hsieh TC, Wu JM.   Grape-derived chemopreventive agent resveratrol
decreases prostate-specific antigen (PSA) expression in LNCaP cells by an
androgen receptor (AR)-independent mechanism.  Anticancer Res 2000
Jan-Feb;20(1A):225-8. 
6.    Gautam SC, Xu YX, Dumaguin M, Janakiraman N, Chapman RA.  Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging. Bone Marrow Transplant 2000 Mar;25(6):639-45
7.    De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. .Sulphation
of resveratrol, a natural product present in grapes and wine, in the human
liver and duodenum. Xenobiotica 2000 Jun;30(6):609-17 
8.  Delmas D, Jannin B, Malki MC, Latruffe N. Inhibitory effect of
resveratrol on the proliferation of humanand rat hepatic derived cell lines. 
Oncol Rep 2000 Jul-Aug;7(4):847-52.
9.    Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and
function of theandrogen receptor in LNCaP prostate cancer cells. Cancer Res
1999 Dec 1;59(23):5892-5.  
10.   Elattar TM, Virji AS. The effect of red wine and its components on
growth and proliferation of human oral squamous carcinoma cells.   Anticancer Res 1999 Nov-Dec;19(6B):5407-14.
11.   Surh YJ, Hurh YJ, Kang JY, Lee E, Kong G, Lee SJ.  Resveratrol, an
antioxidant present in red wine, inducesapoptosis in human promyelocytic
leukemia (HL-60) cells. Cancer Lett 1999 Jun 1;140(1-2):1-10.   
12.   Jang M, Pezzuto JM. Cancer chemopreventive activity of resveratrol. 

References from Current Newsletter:  
Drugs Exp Clin Res 1999;25(2-3):65-77.

[1] Pancreas 2002 Nov;25(4):e71-6. Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Ding XZ, Adrian TE.

[2] Blood 2003 Apr 10; [epub ahead of print]Resveratrol blocks interleukin-1{beta}-induced activation of the nuclear transcription factor NF-{kappa}B, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Estrov Z, Shishodia S, Faderl S, Harris D, Van Q, Kantarjian HM, Talpaz M, Aggarwal BB.

[3] Carcinogenesis 2002 Aug;23(8):1327-33. Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells. Ferry-Dumazet H, Garnier O, Mamani-Matsuda M, Vercauteren J, Belloc F, Billiard C, Dupouy M, Thiolat D, Kolb JP, Marit G,Reiffers J, Mossalayi MD.

[4] Leuk Lymphoma 2002 May;43(5):983-7 Anti-leukemia effect of resveratrol. Tsan MF, White JE, Maheshwari JG, Chikkappa G.

[5] World J Gastroenterol 2003 Mar;9(3):408-11
Resveratrol induces apoptosis in human esophageal carcinoma cells.
Zhou HB, Yan Y, Sun YN, Zhu JR.

[6] Cancer Lett 2003 Feb 20;190(2):157-63. Resveratrol is a potent inducer of apoptosis in human melanoma cells. Niles RM, McFarland M, Weimer MB, Redkar A, Fu YM, Meadows GG.

[7] Urol Oncol 2002 Nov-Dec;7(6):223-7. Resveratrol-A prostate cancer chemopreventive agent? . Ratan HL, Steward WP, Gescher AJ, Mellon JK.

[8] J Urol 2002 Aug;168(2):748-55. Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. Lin HY, Shih A, Davis FB, Tang HY, Martino LJ, Bennett JA, Davis PJ.

[9] Curr Med Chem Anti-Canc Agents 2003 Mar;3(2):77-93
Resveratrol and cancer: chemoprevention, apoptosis, and chemo-immunosensitizing activities. Cal C, Garban H, Jazirehi A, Yeh C, Mizutani Y, Bonavida B.

[10] Int J Cancer 2002 Apr 10;98(5):761-9  Food-derived polyphenols inhibit pancreatic cancer growth through mitochondrial cytochrome C release and apoptosis. Mouria M, Gukovskaya AS, Jung Y, Buechler P, Hines OJ, Reber HA, Pandol SJ.