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6)http://www.ncbi.nlm.nih.gov/pubmed/23411350

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Anti-Cancer Activity from Plant Pterostilbenes by Jeffrey Dach MD

Pterostilbene_Metastases-Associated_Protein_1_Tumor_inhibition2

Anti-Cancer Activity from Natural Plant Pterostilbenes

by Jeffrey Dach MD

Epidemiological studies showing a diet high in fruits and vegetables reduced cancer risk sparked interest in commonly available foods as anti-cancer agents.
Above left image: Inhibition of cancer growth. Male Mice were injected with Prostate Cancer cells, and then treated with placebo (CTRL – controls upper row), Resveratrol (RES – middle row) or Pterostilbene (PTER lower row) . Color intensity shows cancer inhibition by Res and PTER. (5)
In 1997, Jang reported in Science the anti-cancer effects of Resveratrol, present in grapes and berries, which then became the focus for interest as an anti-cancer, anti-inflammatory, and anti-aging food supplement.

Resveratrol Analogs

In recent years, a number of analogs of Resveratrol called stilbenes have been recognized as more suitable as anti-cancer agents. In particlular, Piceatannol a hydroxykated version of Resveratrol and Pterostilbene a methoxylated version of Resveratrol have been the focus of a flurry of research activity showing in-vitro and in- vivo considerable anti-cancer activity. Pterostilbene is available at the vitamin store as a food supplement. This article will explain and summarize some of these studies.

Left Image : Pterostilbene , available as a Nutritional Supplement, Photo courtesy of Source Naturals.

The USDA

The USDA and the University of Mississippi have been studying Resveratrol analogs for more than a decade, and in 2002, reported inhibition of breast cancer in a mouse model (1). This same group delved into the molecular biology of Pterostilbene’s anti-cancer activity and came out with two important papers this year (in 2013) (4,5).
In the first paper, the authors examined the anti-cancer activity of various analogs of Resveratrol (Piceatannol, and 3M-Resveratrol) in prostate cancer cells, both of which showed higher potency in inhibiting tumor progression compared to Resveratrol itself. They concluded that their “findings offer strong pre-clinical evidence for the utilization of dietary stilbenes, particularly 3M-Res, as novel, potent, effective chemopreventive agents in prostate cancer“.(4)

Pterostilbene IS The Most Promising

In their next study, Dr Li reports that Pterostilbene appears to be the most promising of the Resveratrol analogs, which significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis in a mouse model of prostate cancer. (5)

Additional studies have been done on other cancers such as Lung Cancer (7,10) Breast Cancer (8,9,11,16) Colon Cancer (13) skin cancer (20) and Leukemia (17).
Left Image is chemical structure of Pterostilbene courtesy of wikimedia commons

Conclusion: Pterostilbene is a compound found in grapes and berries which have striking anti-cancer activity in animal models through mechanisms elucidated by modern molecular biology. These are not drugs. Rather, they are safe food supplements available at the vitamin store without a prescription. Other health benefits such as blood sugar control, lipid control and blood pressure modulation will be the topic for part two of this series.

Articles with related interest:

Salvestrols Part One
Salvestrols Part Two
Iodine for Breast Cancer Prevention and Treatment

Links and References

2002 – USDA U of Miss- Mammary CA in mouse model inhibited by Reveratrol and Pterostilbene

1) http://www.ncbi.nlm.nih.gov/pubmed/12033810
J Agric Food Chem. 2002 Jun 5;50(12):3453-7. Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol. Rimando AM, Cuendet M, Desmarchelier C, Mehta RG, Pezzuto JM, Duke SO. Natural Products Utilization Research Unit, Agricultural Research Service, U.S. Department of Agriculture, P.O. Box 8048, University, Mississippi 38677, USA.

Pterostilbene, a natural methoxylated analogue of resveratrol, was evaluated for antioxidative potential. The peroxyl-radical scavenging activity of pterostilbene was the same as that of resveratrol, having total reactive antioxidant potentials of 237 +/- 58 and 253 +/- 53 microM, respectively. Both compounds were found to be more effective than Trolox as free radical scavengers. Using a plant system, pterostilbene also was shown to be as effective as resveratrol in inhibiting electrolyte leakage caused by herbicide-induced oxidative damage, and both compounds had the same activity as alpha-tocopherol. Pterostilbene showed moderate inhibition (IC50 = 19.8 microM) of cyclooxygenase (COX)-1, and was weakly active (IC50 = 83.9 microM) against COX-2, whereas resveratrol strongly inhibited both isoforms of the enzyme with IC50 values of approximately 1 microM. Using a mouse mammary organ culture model, carcinogen-induced preneoplastic lesions were, similarly to resveratrol, significantly inhibited by pterostilbene (ED50 = 4.8 microM), suggesting antioxidant activity plays an important role in this process.
2010
2) Pterostilbene_Monograph_Altern_Med_Review_July_2010
Altern Med Rev. 2010 Jul;15(2):159-63.
Pterostilbene. Monograph.[No authors listed] – Excellent Review Article
2012
3) http://www.ncbi.nlm.nih.gov/pubmed/22099605
J Surg Res. 2012 Apr;173(2):e53-61. doi: 10.1016/j.jss.2011.09.054. Epub 2011 Oct 21.
Pterostilbene and cancer: current review. McCormack D, McFadden D.Department of Surgery, Danbury Hospital, Danbury, Connecticut 06810, USA.
Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is an antioxidant that is primarily found in blueberries. Studies suggest that pterostilbene exhibits the hallmark characteristics of an effective anticancer agent based on its antineoplastic properties in several common malignancies. In vitro models have shown that pterostilbene inhibits cancer growth through alteration of the cell cycle, induction of apoptosis, and inhibition of metastasis. In vivo, pterostilbene inhibits tumorigenesis and metastasis with negligible toxicity. Pterostilbene has also been shown to be effective as an inducer of antioxidant capacity in multiple cancer cell lines that may facilitate its function as an anticarcinogenic compound. Additionally, preliminary studies show that pterostilbene exhibits much greater bioavailability compared with other stilbene compounds; however the exact pharmacologic mechanism of pterostilbene and its effects in humans are still under investigation. In this review, we present a comprehensive summary of the antineoplastic mechanisms of pterostilbene based on the results of preclinical studies and highlight recent advances in the study of this dietary compound.
2013
They examined the anti-proliferative activities of Res/analogues in three PCa cell lines

4) http://onlinelibrary.wiley.com/doi/10.1002/pros.22657/
Dias, Steven J., et al. “Trimethoxy‐Resveratrol and Piceatannol Administered Orally Suppress and Inhibit Tumor Formation and Growth in Prostate Cancer Xenografts.” The Prostate (2013).U.S. Department of Agriculture, University of Mississippi

Resveratrol (Res) is recognized as a promising cancer chemoprevention dietary polyphenol with antioxidative, anti-inflammatory, and anticancer properties. However, the role of its analogues in prostate cancer (PCa) chemoprevention is unknown.
METHODS We synthesized several natural and synthetic analogues of Res and characterized their effects on PCa cells in vitro using a cell proliferation assay. A colony formation assay and in vitro validation of luciferase (Luc) activity was done for LNCaP-Luc cells that were consequently used for in vivo studies. The efficacy of Res, trimethoxy-resveratrol (3M-Res) and piceatannol (PIC) was studied in a subcutaneous (s.c.) model of PCa using oral gavage. Tumor progression was monitored by traditional caliper and bioluminescent imaging. The levels of cytokines in serum were examined by ELISA, and the levels of compounds in serum and tumor tissues were determined by gas chromatography-mass spectrometry.
RESULTS We examined the anti-proliferative activities of Res/analogues in three PCa cell lines. We further compared the chemopreventive effects of oral Res, 3M-Res, and PIC in LNCaP-Luc-xenografts. We found that 2 weeks pretreatment with the compounds diminished cell colonization, reduced tumor volume, and decreased tumor growth in the xenografts. Both 3M-Res and PIC demonstrated higher potency in inhibiting tumor progression compared to Res. Notably, 3M-Res was the most active in inhibiting cell proliferation and suppressing colony formation, and its accumulation in both serum and tumor tissues was the highest.
CONCLUSIONS Our findings offer strong pre-clinical evidence for the utilization of dietary stilbenes, particularly 3M-Res, as novel, potent, effective chemopreventive agents in PCa. Prostate

5) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586048/
Li, K., Dias, S. J., Rimando, A. M., Dhar, S., Mizuno, C. S., Penman, A. D., … & Levenson, A. S. (2013). Pterostilbene Acts through Metastasis-Associated Protein 1 to Inhibit Tumor Growth, Progression and Metastasis in Prostate Cancer.

PloS one, 8(3), e57542.Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.

We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1), which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex that mediates gene silencing.

We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER), found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent.

In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis.

Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.

Am J Surg. 2013 Apr;205(4):483.Pterostilbene and its emerging antineoplastic effects: a prospective treatment option for systemic malignancies. Kapoor S.
7)   http://www.bioportfolio.com/resources/pmarticle/383498/Chemopreventive-Effects-of-Pterostilbene-on-Urethane-Induced-Lung-Carcinogenesis-in-Mice-via.html
Chemopreventive Effects of Pterostilbene on Urethane-Induced Lung Carcinogenesis in Mice via the Inhibition of EGFR-Mediated Pathways and the Induction of Apoptosis and Autophagy. Department of Environmental and Occupational Health, National Cheng Kung University Medical College , Tainan, Taiwan.
Journal of agricultural and food chemistry
The aim of this study is to investigate the chemopreventive effects of pterostilbene in urethane-induced murine lung tumors. Pretreatment with pterostilbene at 50 or 250 mg/kg significantly reduced tumor multiplicity by 26 and 49%, respectively. Pterostilbene also significantly inhibited tumor volume by 25 and 34% and decreased the tumor burden per mouse by 45 and 63%, respectively.
2012
8) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276376/
http://www.ncbi.nlm.nih.gov/pubmed/22347521
Am J Transl Res. 2012;4(1):44-51. Epub 2012 Jan 5.
Pterostilbene simultaneously induces apoptosis, cell cycle arrest and cyto-protective autophagy in breast cancer cells.Wang Y, Ding L, Wang X, Zhang J, Han W, Feng L, Sun J, Jin H, Wang XJ.
As a nature phytoalexin found in grapes, resveratrol has been proposed as a potential drug for cancer chemoprevention and treatment. However, its poor bioavailability limits its potential clinical application. Pterostilbene, the natural dimethylated analog of resveratrol with greater bioavailability, was confirmed to inhibit tumor growth both in vivo and in vitro, demonstrating its potential for further clinical application. In the current study, we found that pterostilbene could markedly inhibit the growth of two independent breast cancer cell lines. Both apoptosis and cell cycle arrest as well as the inhibition of wnt singling was induced by pterostilbene. The dominant-active mutant of ß-catenin could reverse the growth inhibitory effect of pterostilbene, indicating that the inhibition of wnt signaling is important to the growth inhibitory effect of pterostilbene. Interestingly, pterostilbene induced autophagy and blockage of autophagy augmented pterostilbene-induced growth inhibition, suggesting that the combination of autophagy inhibitors with pterostilbene and other therapeutics such as endocrine drugs could serve as a new and promising strategy for the treatment of breast cancer cells.
2012
9) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434130/
http://www.ncbi.nlm.nih.gov/pubmed/22957077
PLoS One. 2012;7(9):
Pterostilbene-induced tumor cytotoxicity: a lysosomal membrane permeabilization-dependent mechanism. Mena S, Rodríguez ML, Ponsoda X, Estrela JM, Jäättela M, Ortega AL. Source Green Molecular, Valencia, Spain.
The phenolic phytoalexin resveratrol is well known for its health-promoting and anticancer properties. Its potential benefits are, however, limited due to its low bioavailability. Pterostilbene, a natural dimethoxylated analog of resveratrol, presents higher anticancer activity than resveratrol. The mechanisms by which this polyphenol acts against cancer cells are, however, unclear. Here, we show that pterostilbene effectively inhibits cancer cell growth and stimulates apoptosis and autophagosome accumulation in cancer cells of various origins. However, these mechanisms are not determinant in cell demise.
Pterostilbene promotes cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 (HSP70) content, a known stabilizer of lysosomal membranes. A375 melanoma and A549 lung cancer cells with low levels of HSP70 showed high susceptibility to pterostilbene, whereas HT29 colon and MCF7 breast cancer cells with higher levels of HSP70 were more resistant. Inhibition of HSP70 expression increased susceptibility of HT29 colon and MCF7 breast cancer cells to pterostilbene. Our data indicate that lysosomal membrane permeabilization is the main cell death pathway triggered by pterostilbene.
2013
10) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3643961/
http://www.ncbi.nlm.nih.gov/pubmed/23671619
PLoS One. 2013 May 3;8(5) Pterostilbene Exerts Antitumor Activity via the Notch1 Signaling Pathway in Human Lung Adenocarcinoma Cells. Yang Y, Yan X, Duan W, Yan J, Yi W, Liang Z, Wang N, Li Y, Chen W, Yu S, Jin Z, Yi D. Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an City, China.
In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment.
2010
11) http://www.ncbi.nlm.nih.gov/pubmed/20031172
J Surg Res. 2010 Jun 15;161(2):195-201.
Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis. Alosi JA, McDonald DE, Schneider JS, Privette AR, McFadden DW. University of Vermont, Burlington, Vermont, USA.
Epidemiologic studies suggest that diets high in fruits and vegetables reduce cancer risk. Resveratrol, a compound present in grapes, has been shown to inhibit a variety of primary tumors. Pterostilbene, an analogue of resveratrol found in blueberries, has both antioxidant and antiproliferative properties. We hypothesized that pterostilbene would induce apoptosis and inhibit breast cancer cell growth in vitro.
METHODS:   Breast cancer cells were treated with graduated doses of pterostilbene. Cell viability was measured by MTT assay. Apoptosis was evaluated via DNA fragmentation assay and TUNEL assay. Apo-ONE caspase-3/7 assay was used to evaluate caspase activity. Flow cytometry was used to evaluate mitochondrial depolarization, superoxide formation, and cell cycle. Student’s t-test and two-way ANOVA with Bonferroni posttests were utilized for statistical analysis.
RESULTS: Pterostilbene decreased breast cancer cell viability in a concentration- and time-dependent manner. Pterostilbene treatment increased caspase-3/7 activity and apoptosis in both cell lines. Caspase-3/7 inhibitors completely reversed pterostilbene’s effects on cell viability. Pterostilbene treatment triggered mitochondrial depolarization, increased superoxide anion, and caused alteration in cell cycle.
CONCLUSIONS: Pterostilbene treatment inhibits the growth of breast cancer in vitro through caspase-dependent apoptosis. Mitochondrial membrane
depolarization and increased superoxide anion may contribute to the activation downstream effector caspases. Caspase inhibition leads to complete reversal of pterostilbene’s effect on cell viability. Further in vitro mechanistic studies and in vivo experiments are warranted to determine its potential for the treatment of breast cancer.
2006
12) Pharmacometrics_of_Pterostilbenes_Curr_Clin_Pharmacol_2006_Davies
Curr Clin Pharmacol. 2006 Jan;1(1):81-101.
Pharmacometrics of stilbenes: seguing towards the clinic.
Roupe KA, Remsberg CM, Yáñez JA, Davies NM.
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6534, USA.
Stilbenes are small molecular weight (approximately 200-300 g/mol), naturally occurring compounds and are found in a wide range of plant sources, aromatherapy products, and dietary supplements. These molecules are synthesized via the phenylpropanoid pathway and share some structural similarities to estrogen. Upon environmental threat, the plant host activates the phenylpropanoid pathway and stilbene structures are produced and subsequently secreted. Stilbenes act as natural protective agents to defend the plant against viral and microbial attack, excessive ultraviolet exposure, and disease. One stilbene, resveratrol, has been extensively studied and has been shown to possess potent anti-cancer, antiinflammatory and anti-oxidant activities. Found primarily in the skins of grapes, resveratrol is synthesized by Vitis vinifera grapevines in response to fungal infection or other environmental stressors. Considerable research showing resveratrol to be an attractive candidate in combating a wide variety of cancers and diseases has fueled interest in determining the disease-fighting capabilities of other structurally similar stilbene compounds. The purpose of this review is to describe four such structurally similar stilbene compounds, piceatannol, pinosylvin, rhapontigenin, and pterostilbene and detail some current pharmaceutical research and highlight their potential clinical applications.
13) Pterostilbene_suppresses_aberrant_crypt_colon_carcinogenesis
Clin Cancer Res. 2007 Jan 1;13(1):350-5.
Pterostilbene, an active constituent of blueberries, suppresses aberrant crypt foci formation in the azoxymethane-induced colon carcinogenesis model in rats.
Suh N, Paul S, Hao X, Simi B, Xiao H, Rimando AM, Reddy BS.
Source Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Epidemiologic studies have linked the consumption of fruits and vegetables to reduced risk of several types of cancer. Laboratory animal model studies have provided evidence that stilbenes, phenolic compounds present in grapes and blueberries, play a role in inhibiting the risk of certain cancers. Pterostilbene, a naturally occurring stilbene from blueberries, was tested for its preventive activity against colon carcinogenesis.
EXPERIMENTAL DESIGN: Experiments were designed to study the inhibitory effect of pterostilbene against the formation of azoxymethane-induced colonic aberrant crypt foci (ACF) preneoplastic lesions in male F344 rats. Beginning at 7 weeks of age, rats were treated with azoxymethane (15 mg/kg body weight s.c., once weekly for 2 weeks). One day after the second azoxymethane treatment, rats were fed experimental diets containing 0 or 40 ppm of pterostilbene. At 8 weeks after the second azoxymethane treatment, all rats were sacrificed, and colons were evaluated for ACF formation and for inhibition of inducible nitric oxide synthase (iNOS) and proliferating cell nuclear antigen. Effects on mucin MUC2 were also determined.
RESULTS: Administration of pterostilbene for 8 weeks significantly suppressed azoxymethane-induced formation of ACF (57% inhibition, P < 0.001) and multiple clusters of aberrant crypts (29% inhibition, P < 0.01). Importantly, dietary pterostilbene also suppressed azoxymethane-induced colonic cell proliferation and iNOS expression. Inhibition of iNOS expression by pterostilbene was confirmed in cultured human colon cancer cells.
CONCLUSIONS: The results of the present study suggest that pterostilbene, a compound present in blueberries, is of great interest for the prevention of colon cancer.
14) Pharmacometrics_of_pterostilbene_Phytother_Res_2008
Phytother Res. 2008 Feb;22(2):169-79. Pharmacometrics of pterostilbene: preclinical pharmacokinetics and metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity. Remsberg CM, Yáñez JA, Ohgami Y, Vega-Villa KR, Rimando AM, Davies NM. Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University Pullman, Washington 99164-6534, USA.
The present study evaluated the preclinical pharmacokinetics and pharmacodynamics of trans-pterostilbene, a constituent of some plants. Right jugular vein cannulated male Sprague-Dawley rats were dosed i.v. with 20 mg/kg of pterostilbene and samples were analysed by the reverse phase HPLC method. Serum AUC, serum t(1/2), urine t(1/2), Cl(total) and Vd(beta) were 17.5 +/- 6.6 microg/h/mL, 1.73 +/- 0.78 h, 17.3 +/- 5.6 h, 0.960 +/- 0.025 L/h/kg and 2.41 +/- 1.13 L/kg (mean +/- SEM), respectively. A pterostilbene glucuronidated metabolite was detected in both serum and urine. The in vitro metabolism in rat liver microsomes furthermore suggests phase II metabolism of pterostilbene. Pterostilbene demonstrated concentration-dependent anticancer activity in five cancer cell lines (1-100 microg/mL). An in vitro colitis model showed concentration-dependent suppression of PGE(2) production in the media of HT-29 cells. Antiinflammatory activity was examined by inducing inflammation in canine chondrocytes followed by treatment with pterostilbene (1-100 microg/mL). The results showed decreased levels of MMP-3, sGAG and TNF-alpha compared with control levels. Pterostilbene exhibited concentration-dependent antioxidant capacity measured by the ABTS method. Pterostilbene increased the latency period to response in both tail-flick and hot-plate analgesic tests.
15) Resveratrol_derivatives_cancer_Drug_Discov_Today_2010_Fulda
Drug Discov Today. 2010 Sep;15(17-18):757-65.
Resveratrol and derivatives for the prevention and treatment of cancer. Fulda S.   Institute for Experimental Cancer Research in Pediatrics, Goethe-University, D-60528 Frankfurt, Germany.
There are several natural derivatives of resveratrol that are structurally similar to resveratrol and are also present in food. Such resveratrol derivatives might provide promising tools as cancer chemopreventive agents, as well as cancer therapeutics in the prevention and treatment of cancer. This review provides an overview of key derivatives of resveratrol as cancer therapeutics.
16) http://www.hindawi.com/journals/ecam/2011/562187/
Evidence-Based Complementary and Alternative Medicine Volume 2011 (2011), Suppression of Heregulin-β1/HER2-Modulated Invasive and Aggressive Phenotype of Breast Carcinoma by Pterostilbene via Inhibition of Matrix Metalloproteinase-9, p38 Kinase Cascade and Akt Activation
Min-Hsiung Pan,1 Ying-Ting Lin,2 Chih-Li Lin,3 Chi-Shiang Wei,2 Chi-Tang Ho,4 and Wei-Jen Chen21Department of Seafood Science, National Kaohsiung Marine University, Nan-Tzu, Kaohsiung, Taiwan 2Department of Biomedical Sciences, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo N. Road, Taichung 402, Taiwan 3Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan 4Department of Food Science, Cook College, Rutgers University, New Brunswick, NJ, USA
17) Pterostilbene_apoptosis_ leukemia
http://www.ncbi.nlm.nih.gov/pubmed/23264221
Folia Histochem Cytobiol. 2012;50(4):574-80.
Pterostilbene induces cell cycle arrest and apoptosis in MOLT4 human leukemia cells.
Siedlecka-Kroplewska K, Jozwik A, Kaszubowska L, Kowalczyk A, Boguslawski W.
Department of Histology, Medical University of Gdansk, Gdansk, Poland.
Pterostilbene, a polyphenolic compound present in grapes and other fruits, has been demonstrated to inhibit growth and induce apoptosis and autophagy in some cancer cell types. We found that pterostilbene at the IC(90) concentration of 44 µM inhibited proliferation and induced apoptosis in MOLT4 human leukemia cells. Treatment with pterostilbene resulted in a transient accumulation of cells in the G(0)/G(1)-cell cycle phase followed by the S-phase arrest. Pterostilbene-induced apoptotic death of MOLT4 cells was mediated by caspase-3 activation and was accompanied by the disruption of mitochondrial membrane potential, phosphatidylserine externalization and internucleosomal DNA fragmentation. Our results suggest that pterostilbene could serve as a potential additional chemotherapeutic agent for the treatment of leukemia.
commercial product monograph
18) Natural-Pterostilbene “NATURAL PTEROSTILBENE.” by MAJEED, MUHAMMED.
19) http://clincancerres.aacrjournals.org/content/16/24/5942.long
Clin Cancer Res. 2010 Dec 15;16(24):5942-8.
Resveratrol: challenges in translation to the clinic–a critical discussion.Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR.Department of Ophthalmology and Visual Sciences, Eye Research Institute, and Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin 53792, USA.
Abstract
Low cancer survival rates and the serious side effects often associated with current chemotherapeutics highlight the need for new and effective nontoxic anticancer agents. Since 1997 when Jang and colleagues first described resveratrol’s ability to inhibit carcinogenesis, it has consistently proven effective at tumor inhibition in diverse human cancer models. This finding has raised the hope that resveratrol would pioneer a novel class of nontoxic chemotherapeutics. As a consequence of initial basic and preclinical studies, resveratrol is now being extensively promoted in the unregulated nutraceutical sector. However, some fundamental aspects of resveratrol’s action need to be understood before it can be developed into a clinically viable anticancer drug. These areas pertain to the key mechanism(s) by which resveratrol potentiates its antitumor effects. Current research suggests that these mechanisms might be through novel pathways, requiring an understanding of cellular uptake, sentinel targets, and in vivo biological networks. The metabolism of resveratrol and its bioavailability also warrant further consideration in light of recent in vitro and in vivo studies. Finally, we need to appreciate the sorts of information about resveratrol that may translate between different disease entities. We present a critical discussion of these issues and suggest important experiments that could pave the way to the successful translation of resveratrol to the clinic.
20) http://www.ncbi.nlm.nih.gov/pubmed/22842666
Food Funct. 2012 Nov;3(11):1185-94. Pterostilbene, a natural analogue of resveratrol, potently inhibits 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis. Tsai ML, Lai CS, Chang YH, Chen WJ, Ho CT, Pan MH.Department of Seafood Science, National Kaohsiung Marine University, Nan-Tzu, Kaohsiung 811, Taiwan. mltasi@mail.nkmu.eud.tw
Abstract
We reported previously that pterostilbene, a natural analogue of resveratrol from blueberries, strongly suppressed lipopolysaccharide-induced up-expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in murine macrophages. In this study, we further investigated pterostilbene’s molecular mechanism of action and its anti-tumor properties. Pretreatment with pterostilbene has resulted in the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced nuclear translocation of the nuclear factor-κB (NFκB) subunits. Pterostilbene also reduced TPA-induced phosphorylation of IκBα and p65 and caused subsequent degradation of IκBα. Moreover, pterostilbene markedly suppressed TPA-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK)1/2, phosphatidylinositol 3-kinase (PI3K) and Akt, which are upstream of NFκB and activator protein 1 (AP-1). Furthermore, pterostilbene significantly inhibited 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. The presented data has, for the first time, revealed that pterostilbene is an effective anti-tumor agent that functions by downregulating inflammatory iNOS and COX-2 gene expression in mouse skin. It is suggested that pterostilbene is a novel functional agent capable of preventing inflammation-associated tumorigenesis.

Jeffrey Dach MD

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8) http://www.ncbi.nlm.nih.gov/pubmed/22496613

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Copyright (c) 2013 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given.
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The Origin of Bioidentical Hormones by Jeffrey Dach MD

Russell Marker and the Origins of Bioidentical Hormones

by Jeffrey Dach MD

Where do Bioidentical Hormones Come From ?

A couple of times a week, I get the question, “Where do hormones comes from ?” Russell E Marker was the Penn State chemist who originated Progesterone and other Bioidentical Hormones from a plant steroid called Diosgenin. (upper left image Russell Marker courtesy of American Chemical_Society)

Who was Russell Marker ?

Russell Marker was a Penn State chemist in 1938 who invented a practical way to mass produce Progesterone, the pregnancy hormone. using a technique known as the Marker degradation process.

Chemistry Professor at Penn State

In 1938, Marker was a chemistry professor at Pennsylvania State College working on plant steroid chemistry. During this time, Marker found a plant steroid from the Dioscorea family called Diosgenin which could be easily converted into the human bioidentical hormone, Progesterone.
Next, Marker needed an economical source of the plant material to isolate the plant steroid called Diosgenin. (upper left image Russell Markerwith plants courtesy of American Chemical_Society )

Finding the Plant Material in Mexico

In November 1941, Marker found what he had been searching for in a botany textbook describing a Dioscorea plant indigenous to Veracruz in Mexico, called Cabeza de Negro.

Left image: Diosgenin from Diascorea plant Mexican Yam courtesy of wikimedia commons.
In 1942, Marker then traveled to Mexico where he purchased some of the Dioscorea plant material and started the mass production of the bioidentical hormone, Progesterone.
In 1943, Marker resigned from Penn State University and moved to Mexico to begin mass production of Progesterone and other bioidentical hormones. Marker refused to assign patent rights to anyone, including himself, thus granting free use of his invention to anyone interested.

In early 1944, Syntex was formed in Mexico to manufacture Progesterone from the Diascorea Diosgenin. In May 1945, over a dispute, Marker left Syntex and started a new company, Botanica-mex, near Mexico City which then made several kilos of Progesterone. Botanica-mex folded in March 1946, and was restarted as a new company called Hormonosynth. During this time, the cabeza de negro plant source was replaced by another yam called barbasco, containing 500% more diosgenin. After Marker’s retirement, the company was again reorganized as Diosynth.

(upper image Chemcial Diagram of Marker Degradation courtesy of American Chemical_Society_CNBP_027297 )

Syntex After Marker Leaves – Syntex Prospers

After Marker left Syntex , the company recruited another chemist George Rosenkranz, who began October 1945, and Syntex was again selling progesterone.    Rosenkranz extended the process to the production of testosterone and other bioidentical hormones .   Rosenkranz built a research program at Syntex, and recruited other Ph.D. chemists including Carl Djerassi and Alejandro Zaffaroni.

Cortisone and the “Pill”

Further research at Syntex led to discovery that this same plant steroid precursor Diosgenin could be converted to cortisone, a powerful anti-inflammatory steroid. The company also worked on the synthetic birth control pill.   By the 1950s, Syntex and its competitors were the major supplier of bioidentical hormones to the United States.

Health Benefits of Diosgenin

While using Diosgenin as a precursor to progesterone, Russel Marker had no way of knowing that Diosgenin has its own health benefits.   One of which is as a natural anti-cancer drug. Diosgenin also reduces inflammation, serving as an anti-inflammatory drug. Diosgenein also serves as a lipid control drug, with beneficial effects of lipid profiles.

Articles with Related Interest:

The Safety of Bioidentical Hormones
The Importance of Bioidentical Hormones
Bioidentical Hormones Prevent Heart Disease
Bioidentical Hormones Prevent Arthritis

Author: Jeffrey Dach MD

Links and References:

1)http://portal.acs.org/portal/PublicWebSite/education/whatischemistry/landmarks/progesteronesynthesis/index.htm
2) http://portal.acs.org/preview/fileFetch/C/CNBP_027297/pdf/CNBP_027297.pdf

3) http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_ARTICLEMAIN&node_id=926&content_id=CTP_004452&use_sec=true&sec_url_var=region1&__uuid=5aab01fd-b815-4dc5-b156-86688fc64df6
The following pages commemorate the designation of the “Marker Degradation” and creation of the Mexican steroid hormone industry as an International Historic Chemical Landmark. The designation was conferred by the American Chemical Society and the Sociedad Química de México in ceremonies at The Pennsylvania State University, University Park, Pennsylvania, on October 1, 1999, in Monterrey, Mexico, on October 25, 1999, and in Mexico City, Mexico, on December 2, 1999.
4) http://en.wikipedia.org/wiki/Marker_degradation
The Marker degradation is a three-step synthetic route in steroid chemistry developed by American chemist Russell Earl Marker in 1938–40.
5) http://pubs.acs.org/doi/abs/10.1021/ja01869a023
The Marker semi-synthesis of progesterone from diosgenin. Marker RE, Krueger J (1940). “Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone”. J. Am. Chem. Soc. 62 (12): 3349–3350.
6) http://pabook.libraries.psu.edu/palitmap/Prog.html
Road to Hope for Female Infertility: Progesterone
By Stephen T. Spagnol, Spring 2010
7) pdf file:Russell_Marker_Syntex_Progesterone_Chemical_Society_CNBP_027297
THE “MARKER DEGRADATION” AND CREATION OF THE MEXICAN STEROID HORMONE INDUSTRY 1938–1945 AN INTERNATIONAL HISTORIC CHEMICAL LANDMARK UNIVERSITY PARK, PENNSYLVANIA, OCTOBER 1, 1999 , MEXICO CITY, DECEMBER 2, 1999
Jeffrey Dach MD
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www.naturalmedicine101.com
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The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

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FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.

Friday, June 14, 2013

Salvestrols, Part Two by Jeffrey Dach MD

This article is part two of a series.

Click Here for part one.

In part two, we will delve into more detail concerning the biochemistry and molecular biology of Salvestrols based on studies in the medical literature.

Left image courtesy of Dr Kwon in J Nutr Biochem. 2012 (9) Piceatannol inhibits lung mets after injection of prostate cancer cells into mice. Upper row:control animals. Lower row : highest dose of picetannol shows less uptake indicating inhibition of metastatic disease.(9)

In 2000, a Japanese research group discovered that a plant extract found to inhibit a mouse model of lung cancer was actually the compond Piceatannol, a naturally occurring polyphenol present in rhubarb, berries, peanuts, sugar cane, wine and the skins of grapes(1)

Active Ingredient in Salvestrols is Piceatannol – via conversion by the CYP1B1

In 2002, Drs Gerald Potter and Dan Burke reported this same anti-cancer compound, Piceatannol, is a close cousin to Resveratrol.(2) Their 2002 paper in the British Journal of Cancer describes how the CYP 1B1 enzyme present in most cancer cells converts Resveratrol to Piceatannol via hydroxylation at the 4 position of the aromatic ring.(2) They theorized that the CYP1B1 enzyme in tumors may be functioning as a growth suppressor enzyme. (2) The cytochrome enzyme, CYP1B1, is overexpressed in cancer cells and is absent in normal healthy cells. (2)

In 2004, Dr. Larrosa et al found that this same compound, Piceatannol,(left image) is a potent inducer of cell death in human malignant melanoma cancer cells in vitro. (3)

Left Image: Piceatannol chemical structure courtesy of wikimedia commons.

In 2009, A Korean research group found that Piceatannol induces G1 cell cycle arrest in human prostate cancer cells in vitro (4) The authors state: “These results indicate that piceatannol induces apoptosis via the activation of the death receptor and mitochondrial-dependent pathways in prostate cancer cells.” (5)

2012- A Flurry of New Studies

In 2012, Dr Morales from Madrid studied the apoptotic effects of piceatannol and Myricetin, naturally occurring polyphenols in red wine, alone or in combination, in two human cell lines: HL-60 (leukemia) and HepG2 (hepatoma). The piceatannol and Myricetin synergistically induced apoptosis in HL-60 leukemia cells but not in HepG2 hepatoma cells suggesting that anticarcinogenic effects depend on the cell line used. (6)

In 2012, Dr Piotrowska from Poland published this comment: “Piceatannol has been found in various plants, including grapes, passion fruit, white tea, and Japanese knotweed. Besides antioxidative effects, piceatannol exhibits potential anticancer properties as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including leukemia, lymphoma; cancers of the breast, prostate, colon and melanoma.“(7)

Activity Against Hepatoma Bearing Mice

Piceatannol inhibits hepatoma

Also in 2012, a mouse model of human liver cancer (hepatoma) from Dr. Kita of Japan showed that Piceatannol inhibited progression of tumor size and weight. (see image at left) (8)

Left image shows reduction in tumor size and tumor weght in hepatoma bearing mice treated with Piceatannol. Courtesy of Dr Kita in Antiproliferative and anti-invasive effect of piceatannol against hepatoma. Tokyo, Japan. (8)

The authors state: “results suggest that piceatannol has a potential to suppress the hepatoma proliferation by inducing cell cycle arrest and apoptosis induction. Thus, piceatannol may be a useful anticancer natural product.”

Mouse Imaging Study:

Also in 2012, a Korean research group found that Piceatannol inhibits development of lung mets in a mouse prostate cancer model.. In this study, rat prostate cancer cells were injected into the tail veins of mice. Mice fed piceatannol had significant inhibition of metastases to the lung. (left Image) (9)

Conclusion:

Cancer cells have the CYP 1B1 enzyme which converts Resveratrol to the anti-cancer metabolite Piceatannol, which is also found in a variety of fruits and vegetables. Recent animal studies and in-vitro studies are summarized above showing the potential anti-cancer effects of these natural compounds. Since they are naturally found in the diet, they are not drugs, rather they nutritional supplements with no adverse effects. Unfortunately, as yet, there is no clinical trial data on these compounds. For the present, all we have are the case reports which are summarized in part one of this series.

Another promising Resveratrol Analog called Pterostilbene also shows anti-cancer activity which may even exceed Piceatannol. For Part Three click here.

This article is part two of a series. Click Here for part one.

Articles with Related interest: Iodine for Breast Cancer Prevention and Treatment

Links and References

Piceatannol

2000
1) http://www.ncbi.nlm.nih.gov/pubmed/11062702
Anticancer Res. 2000 Sep-Oct;20(5A):2923-30.
Inhibitory effects of active substances isolated from Cassia garrettiana heartwood on tumor growth and lung metastasis in Lewis lung carcinoma-bearing mice (Part 2).
Kimura Y, Baba K, Okuda H. Source Second Department of Medical Biochemistry, School of Medicine, Ehime University, Japan.
Previously, we reported that a methanol extract (500 mg/kg x 2/day) of the heartwood of Cassia garrettiana inhibited the tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. Furthermore, we isolated the two active substances from the methanol extract of C. garrettiana and identified compound 1 as cassigarol A.
In the present study, compound 2 was identified as 3, 3′, 4, 5′-tetrahydroxy stilbene (piceatannol) based on the 1H-NMR spectral data and products formed by oxidation with potassium permanganate. We examined the active substance (compound 2, piceatannol) and its acetylated derivative on the tumor growth and lung metastasis in LLC-bearing and carcinectomized mice. Piceatannol (50 mg and 100 mg/kg x 2/day) did not affect the tumor growth, while piceatannol acetate (50 mg and 100 mg/kg x 2/day) significantly inhibited the tumor growth.
Piceatannol and its derivative piceatannol acetate inhibited the metastasis to the lung dose-dependently in carcinectomized mice. Moreover, piceatannol and piceatannol acetate prolonged the survival time and increased the survival rate in carcinectomized mice. In addition, piceatannol inhibited the formation of capillary-like networks of human umbilical vein endothelial cells (HUVECs) at the concentrations of 10 to 100 microM, but its acetylated derivative did not. Therefore, it is suggested that the antimetastatic activities of piceatannol might be due to the inhibition of tube formation (angiogenesis) of HUVECs.
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
key 2002 article by Gerald Potter
2) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375304/ free full text
http://www.ncbi.nlm.nih.gov/pubmed/11875742
Br J Cancer. 2002 Mar 4;86(5):774-8.
The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. by Potter GA, Patterson LH, Wanogho E, Perry PJ, Butler PC, Ijaz T, Ruparelia KC, Lamb JH, Farmer PB, Stanley LA, Burke MD. Cancer Drug Discovery Group, School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK. gapotter@dmu.ac.uk
Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here that the cancer preventative agent resveratrol undergoes metabolism by the cytochrome P450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukaemic agent piceatannol. The metabolite was identified by high performance liquid chromatography analysis using fluorescence detection and the identity of the metabolite was further confirmed by derivatisation followed by gas chromatography-mass spectrometry studies using authentic piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumours. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumours may be functioning as a growth suppressor enzyme.
Resveratrol is classified as a phytoestrogen because of its similarity to the endogenous oestrogen estradiol. The molecular relationship between resveratrol and estradiol can be seen by mapping the molecular structure of resveratrol onto the estradiol framework as shown in Figure 1B. Because of this relationship we reasoned that resveratrol may also undergo aromatic hydroxylation by CYP1B1. Furthermore we rationalised that aromatic hydroxylation at the position corresponding to that of 4-hydroxyestradiol would generate the tyrosine kinase inhibitor piceatannol. We have used this type of mapping to design novel CYP1B1 activated tyrosine kinase inhibitor prodrugs for tumour selective cancer therapy using our concept of aromatic hydroxylation activation, and these prodrugs are based on the stilbene structure (Potter et al, 2001). We then realised the similarity in molecular structure of the anticancer prodrugs we had designed specifically for CYP1B1 to the molecular structure of certain natural products that have cancer preventative properties, and in particular the phytoestrogens such as resveratrol. This then led us to formulate a hypothesis for the functional role of CYP1B1 as a tumour suppressor enzyme or ‘rescue enzyme’ wherein CYP1B1 serves to activate certain non-toxic dietary components into growth inhibitory substances specifically within tumour cells containing the CYP1B1 enzyme. In this pilot study, we report here that resveratrol is indeed metabolised by CYP1B1 to generate the antileukaemic agent piceatannol.
Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene)
Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene) (Fig. 1) is a naturally occurring polyphenol present in rhubarb, berries, peanuts, sugar cane, wine and the skins of grapes.
2004
3) http://www.ncbi.nlm.nih.gov/pubmed/15309446
Eur J Nutr. 2004 Oct;43(5):275-84. Epub 2004 Jan 12.
The grape and wine polyphenol piceatannol is a potent inducer of apoptosis in human SK-Mel-28 melanoma cells.Larrosa M, Tomás-Barberán FA, Espín JC.
Research Group on Quality, Safety and Bioactivity of Plant Foods, Dep. of Food Science and Technology, CEBAS-CSIC, 164, 30100 Campus de Espinardo (Murcia), Spain.
The resveratrol analogue piceatannol (3,5,3′,4′-tetrahydroxy- trans-stilbene; PICE) is a polyphenol present in grapes and wine. PICE is a protein kinase inhibitor that modifies multiple cellular targets exerting immunosuppressive, antileukemic and antitumorigenic activities in several cell lines and animal models. The present work aims to evaluate the antimelanoma effect of PICE on human melanoma cells for the first time. To this purpose, the pro-apoptotic capacity, uptake and metabolism of PICE as well as its effect on cell cycle and cyclins A, E and B1 expression will be studied.
METHODS:. Human SK-Mel-28 melanoma cells were incubated with PICE (1-200 microM) for 72 hours. Cell cycle and viability were examined using flow cytometry analysis. Apoptosis was determined using the annexin V assay and also by fluorescence microscopy. Cyclins A, E and B1 were detected by Western blotting. Stability, cellular uptake and metabolism of PICE were evaluated using HPLC-DAD-MS-MS.
RESULTS:The lowest PICE concentration assayed (1 microM) increased about 6-fold over the control the apoptotic population of melanoma cells (10.2% at 8 hours which remained constant during 48 h). 100 microM PICE induced 13% apoptosis at 8 h increasing up to 41.5% at 48 h. The decrease in cell viability was highly correlated with the increase of apoptotic cells ( R = 0.996; P < 0.0001) revealing that significant cytotoxic, unspecific effects did not occur in melanoma cells upon incubation with PICE. Cell cycle was arrested at G(2) phase which was supported by the down-regulation of cyclins A, E and B1. Two methyl-PICE derived metabolites, 3,5,4′-trihydroxy-3′-methoxy- trans-stilbene and 3,5,3′-trihydroxy-4′-methoxy- trans-stilbene (corresponding to 36% of the initially PICE added) were excreted by cells to the medium. The same methyl-PICE derivatives were also found inside the cells (0.01% of the initially PICE added; 0.0183 picograms/cell).
CONCLUSION: The antimelanoma properties of dietary piceatannol cannot be ruled out taking into account its fast and potent pro-apoptotic capacity at low concentration (1 microM).

2009

4) http://www.ncbi.nlm.nih.gov/pubmed/19487074
Cancer Lett. 2009 Nov 28;285(2):166-73.
Piceatannol, a natural stilbene from grapes, induces G1 cell cycle arrest in androgen-insensitive DU145 human prostate cancer cells via the inhibition of CDK activity. Lee YM, Lim do Y, Cho HJ, Seon MR, Kim JK, Lee BY, Park JH.
Source. Department of Food Science and Nutrition, Hallym University, Chuncheon 200-702, Republic of Korea.
We have examined whether and by what mechanism piceatannol inhibits cell cycle progression in DU145 cells. The treatment of cells with piceatannol for 24h resulted in an increase in the percentage of cells in G1 phase and dose-dependent decreases in [(3)H]thymidine incorporation, as well as in protein levels of cyclin A, cyclin D1, and cyclin-dependent kinase (CDK)2 and CDK4. Piceatannol exerted no effect on the levels of p21(WAF1/CIP1) or p27(KIP1). Piceatannol reduced CDK4 and CDK2 activity. These results indicate that delaying G1 cell cycle progression contributes to the piceatannol-mediated inhibition of DU145 cell growth, which may be mediated via the inhibition of CDK activity.

5) http://www.ncbi.nlm.nih.gov/pubmed/19857055
J Med Food. 2009 Oct;12(5):943-51. The grape component piceatannol induces apoptosis in DU145 human prostate cancer cells via the activation of extrinsic and intrinsic pathways. Kim EJ, Park H, Park SY, Jun JG, Park JH. Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Chuncheon, Republic of Korea.

Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene) is a polyphenol that is found in grapes, red wine, Rheum undulatum, and the seeds of Euphorbia lagascae. It has been previously reported that piceatannol inhibits the proliferation of a variety of cancer cell types. In the present study, we assessed the effects of piceatannol on the growth of androgen-insensitive DU145 prostate cancer cells at concentrations of 1-10 micromol/L.Piceatannol reduced the viable numbers and increased the numbers of apoptotic DU145 cells in a dose-dependent manner. Western blot analysis revealed that piceatannol increased the protein levels of cleaved caspase-8, -9, -7, and -3 and cleaved poly(ADP-ribose) polymerase (PARP). Piceatannol increased mitochondrial membrane permeability and cytochrome c release from the mitochondria to the cytosol. Piceatannol induced an increase in the levels of truncated Bid, Bax, Bik, Bok, and Fas but caused a decrease in the levels of Mcl-1 and Bcl-xL. Caspase-8 and -9 inhibitors mitigated piceatannol-induced apoptosis. The caspase-8 inhibitor suppressed the piceatannol-induced cleavage of Bid, caspase-3, and PARP. These results indicate that piceatannol induces apoptosis via the activation of the death receptor and mitochondrial-dependent pathways in prostate cancer cells.

2012

6) http://www.ncbi.nlm.nih.gov/pubmed/21935971
J Appl Toxicol. 2012 Dec;32(12):986-93.
Selective apoptotic effects of piceatannol and Myricetin in human cancer cells.
Morales P, Haza AI. Source Departamento de Nutrición, Bromatología y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040, Madrid, Spain.
Numerous studies have shown the potential of dietary polyphenols as anticarcinogenic agents. The aim of the present study was to evaluate the apoptotic effects of piceatannol and Myricetin, naturally occurring polyphenols in red wine, alone or in combination, in two human cell lines: HL-60 (leukemia) and HepG2 (hepatoma). Apoptotic cells were identified by chromatin condensation, poly(ADP-ribose) polymerase cleavage and flow cytometry analysis. Results from TUNEL assay showed that piceatannol or myricetin alone induced apoptotic cell death in a concentration- and time-dependent manners in HL-60 cells. Furthermore, in combined treatment the percentage of apoptotic HL-60 cells was significantly higher. Nevertheless, the percentage of TUNEL positive HepG2 cells only was significant after piceatannol treatment and in combined treatment was even lower than in cells treated with piceatannol alone. Moreover, we also studied the relative reactive oxygen species (ROS) production. Our results indicate that apoptosis induced by piceatannol or myricetin occurs through an ROS-independent cell death pathway. In conclusion, piceatannol and myricetin synergistically induced apoptosis in HL-60 cells but not in HepG2 cells. These findings suggest that the potential anticarcinogenic properties of dietary polyphenols depend largely on the cell line used. The relevance of these data needs to be verified in human epidemiological studies.

7) http://www.ncbi.nlm.nih.gov/pubmed/22108298
Mutat Res. 2012 Jan-Mar;750(1)
Biological activity of piceatannol: leaving the shadow of resveratrol.
Piotrowska H, Kucinska M, Murias M. Source Department of Toxicology, Poznan University of Medical Sciences, ul. Dojazd 30, 60-631 Poznan, Poland.

Resveratrol (3,4′,5-trans-trihydroxystilbene), a naturally occurring stilbene, is considered to have a number of beneficial effects, including anticancer, anti-aethrogenic, anti-oxidative, anti-inflammatory, anti-microbial and estrogenic activity.Piceatannol(3, 3′, 4, 5′-trans-trihydroxystilbene), a naturally occurring hydroxylated analogue of resveratrol, is less studied than resveratrol but displays a wide spectrum of biological activity. Piceatannol has been found in various plants, including grapes, passion fruit, white tea, and Japanese knotweed. Besides antioxidative effects, piceatannol exhibits potential anticancer properties as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including leukemia, lymphoma; cancers of the breast, prostate, colon and melanoma.

The growth-inhibitory and proapoptotic effects of piceatannol are mediated through cell-cycle arrest; upregulation of Bid, Bax. Bik, Bok, Fas: P21(WAF1) down-regulation of Bcl-xL; BCL-2, clAP, activation of caspases (-3, -7,- 8, -9), loss of mitochondrial potential, and release of cytochrome c. Piceatannol has been shown to suppress the activation of some transcription factors, including NF-kappaB, which plays a central role as a transcriptional regulator in response to cellular stress caused by free radicals, ultraviolet irradiation, cytokines, or microbial antigens. Piceatannol also inhibits JAK-1, which is a key member of the STAT pathway that is crucial in controlling cellular activities in response to extracellular cytokines and is a COX-2-inducible enzyme involved in inflammation and carcinogenesis. Although piceatannol has been shown to induce apoptosis in cancer cells, there are examples of its anti-apoptotic pro-proliferative activity. Piceatannol inhibits Syk kinase, which plays a crucial role in the coordination of immune recognition receptors and orchestrates multiple downstream signaling pathways in various hematopoietic cells. Piceatannol also binds estrogen receptors and stimulates growth of estrogen-dependent cancer cells. Piceatannol is rapidly metabolized in the liver and is converted mainly to a glucuronide conjugate; however, sulfation is also possible, based on in vitro studies. The pharmacological properties of piceatannol, especially its antitumor, antioxidant, and anti-inflammatory activities, suggests that piceatannol might be a potentially useful nutritional and pharmacological biomolecule; however, more data are needed on its bioavailability and toxicity in humans.

2012

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303635/
J Biomed Biotechnol. 2012;2012:672416.
Antiproliferative and anti-invasive effect of piceatannol, a polyphenol present in grapes and wine, against hepatoma AH109A cells. Kita Y, Miura Y, Yagasaki K.
Department of Applied Biological Chemistry, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.

Piceatannol is a stilbenoid, a metabolite of resveratrol found in red wine. Piceatannol and sera from rats orally given piceatannol were found to dose-dependently suppress both the proliferation and invasion of AH109A hepatoma cells in culture. Its antiproliferative effect was based on cell cycle arrest at lower concentration (25~50 μM) and on apoptosis induction at higher concentration (100 μM). Piceatannol suppressed reactive oxygen species-potentiated invasive capacity by scavenging the intracellular reactive oxygen species.

These results suggest that piceatannol, unlike resveratrol, has a potential to suppress the hepatoma proliferation by inducing cell cycle arrest and apoptosis induction. They also suggest that the antioxidative property of piceatannol, like resveratrol, may be involved in its anti-invasive action. Subsequently, piceatannol was found to suppress the growth of solid tumor and metastasis in hepatoma-bearing rats. Thus, piceatannol may be a useful anticancer natural product.

3.7. Effect of Piceatannol on Sold Tumor Growth and Metastasis in Hepatoma-Bearing Rats
Dietary piceatannol (0.001% and 0.005%) tended to suppress the AH109A tumor size dose-dependently, although significant differences were not seen (Figure 3(A)). Accordingly, at the end of the 20-day treatment period, the weights of solid tumors were lower in the piceatannol-treated groups than in the control group (Figure 3(B)). The solid tumor weight of the 0.005% piceatannol group was significantly reduced from 20.5 ± 4.4 (control) to 9.4 ± 2.5 (0.005% piceatannol group) g/rat, indicating that ca. 54% reduction was attained by 0.005% piceatannol. Numbers of metastatic foci were 0.22, 0.2, and 0 (number/rat) in the control, 0.001%, and 0.005% piceatannol groups, respectively.

Mouse image study !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

9) http://www.ncbi.nlm.nih.gov/pubmed/21497499
J Nutr Biochem. 2012 Mar;23(3):228-38.
Piceatannol inhibits migration and invasion of prostate cancer cells: possible mediation by decreased interleukin-6 signaling. Kwon GT, Jung JI, Song HR, Woo EY, Jun JG, Kim JK, Her S, Park JH. Department of Food Science and Nutrition, Hallym University, Chuncheon, 200-702, Republic of Korea.Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene) is a polyphenol detected in grapes, red wine and Rheum undulatum; it has also been demonstrated to exert anticarcinogenic effects. In this study, in order to determine whether piceatannol inhibits the lung metastasis of prostate cancer cells, MAT-Ly-Lu (MLL) rat prostate cancer cells expressing luciferase were injected into the tail veins of male nude mice. The oral administration of piceatannol (20 mg/kg) significantly inhibited the accumulation of MLL cells in the lungs of these mice. In the cell culture studies, piceatannol was demonstrated to inhibit the basal and epidermal growth factor (EGF)-induced migration and invasion of DU145 cells, in addition to the migration of MLL, PC3 and TRAMP-C2 prostate cancer cells. In DU145 cells, piceatannol attenuated the secretion and messenger RNA levels of matrix metalloproteinase-9, urokinase-type plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). Piceatannol increased the protein levels of tissue inhibitor of metalloproteinase-2 in a concentration-dependent fashion. Additionally, piceatannol inhibited the phosphorylation of signal transducer and activator of transcription (STAT) 3. Furthermore, piceatannol effected reductions in both basal and EGF-induced interleukin (IL)-6 secretion. An IL-6 neutralizing antibody inhibited EGF-induced STAT3 phosphorylation and EGF-stimulated migration of DU145 cells. Interleukin-6 treatment was also shown to enhance the secretion of uPA and VEGF, STAT3 phosphorylation and the migration of DU145 cells; these increases were suppressed by piceatannol. These results demonstrate that the inhibition of IL-6/STAT3 signaling may constitute a mechanism by which piceatannol regulates the expression of proteins involved in regulating the migration and invasion of DU145 cells.FIGURE    Fig. 8. Piceatannol suppresses the lung metastasis of MLL-Luc cells in nude mice. MLLLuc cells were injected into the tail veins of male nude mice. The mice were subjected to daily oral gavage with piceatannol at doses of 0, 10 or 20 mg/kg/d, commencing 1 day after the MLL-Luc injection. Bioluminescence imaging (BLI) was conducted at 3, 6 and 9 days. (A) Representative BLI in mice, which reveals the progression of lung metastasis at different time points after MLL-Luc injection, is shown. The scale on the right of the image indicates the surface radiance (photons/s/cm2/steradian). (B) The signal intensity was quantified as the sum of all detected photon counts/s in the region of interest (mean±S.E.M., n=6). Means without a common letter differ; Pb.05.201310) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622287/
Biomed Res Int. 2013; 2013: 514349.
Published online 2013 March 26. Tumor Growth Limiting Effects of Piceatannol
Shailendra Kapoor*References from Kapoor
1. Kita Y, Miura Y, Yagasaki K. Antiproliferative and anti-invasive effect of piceatannol, a polyphenol present in grapes and wine, against hepatoma AH109A cells. Journal of Biomedicine and Biotechnology. 2012;2012:7 pages.672416 [PMC free article] [PubMed]
2. Hsieh TC, Lin CY, Lin HY, Wu JM. AKT/mTOR as novel targets of polyphenol piceatannol possibly contributing to inhibition of proliferation of cultured prostate cancer cells. ISRN Urology. 2012;2012:8 pages.272697 [PMC free article] [PubMed]
3. Kim EJ, Park H, Park SY, Jun JG, Park JHY. The grape component piceatannol induces apoptosis in du145 human prostate cancer cells via the activation of extrinsic and intrinsic pathways. Journal of Medicinal Food. 2009;12(5):943–951. [PubMed]4. Lee YM, Lim DY, Cho HJ, et al. Piceatannol, a natural stilbene from grapes, induces G1 cell cycle arrest in androgen-insensitive DU145 human prostate cancer cells via the inhibition of CDK activity. Cancer Letters. 2009;285(2):166–173. [PubMed]
5. Kwon GT, Jung JI, Song HR, et al. Piceatannol inhibits migration and invasion of prostate cancer cells: possible mediation by decreased interleukin-6 signaling. Journal of Nutritional Biochemistry. 2012;(3):228–238. [PubMed]
6. Ko HS, Lee HJ, Kim SH, Lee EO. Piceatannol suppresses breast cancer cell invasion through the inhibition of MMP-9: involvement of PI3K/AKT and NF-kappaB pathways. Journal of Agricultural and Food Chemistry. 2012;60:4083–4089. [PubMed]
7. Wolter F, Clausnitzer A, Akoglu B, Stein J. Piceatannol, a natural analog of resveratrol, inhibits progression through the s phase of the cell cycle in colorectal cancer cell lines. Journal of Nutrition. 2002;132(2):298–302. [PubMed]—————————————————————-Commercial preparations of Picetannol11) https://www.caymanchem.com/app/template/Product.vm/catalog/10009366;jsessionid=751C47180926157C1150520F91E308ADPiceatannol Description Resveratrol is a potent phenolic antioxidant found in the skin of grapes and red wine that has anti-proliferative, anti-inflammatory, and cardioprotective properties.1 Piceatannol is a resveratrol analog formed by the cytochrome P450-catalyzed hydroxylation of resveratrol.2
Piceatannol exhibits potent anticancer properties by inducing apoptosis in BJAB Burkitt-like lymphoma cells with an ED50 value of 25 µM.3 Piceatannol also exhibits anti-proliferative and anti-inflammatory effects by inhibiting the activity of a wide range of tyrosine and serine/threonine protein kinases and suppressing NF-κB activation through inhibition of IκBα kinase.4,5
12) http://www.tocris.com/dispprod.php?ItemId=43353#.UbCHqdhaaSo
Piceatannol Biological Activity
Anti-inflammatory, immunomodulatory and antiproliferative agent. Inhibits p56lck and syk protein tyrosine kinases and inhibits TNF-induced NF-κB activation and gene expression. Synthesis results from conversion of resveratrol (Cat. No. 1418) by cytochrome P450 1B1.
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2013
13) http://www.ncbi.nlm.nih.gov/pubmed/23477622
J Med Food. 2013 Mar;16(3):199-205. doi: 10.1089/jmf.2012.0170.
Use of grape polyphenols against carcinogenesis: putative molecular mechanisms of action using in vitro and in vivo test systems. Gollucke AP, Aguiar O Jr, Barbisan LF, Ribeiro DA. HEXALAB and Department of Nutrition, Catholic University of Santos, Sao Paulo, Brazil.
Polyphenols are present in foods and beverages and are related to sensorial qualities such as color, bitterness, and astringency, which are relevant in wine, tea, grape juice, and other products. These compounds occur naturally in forms varying from simple phenolic acids to complex polymerized tannins. Thus, it is reasonable to expect that grape-derived products elaborated in the presence of skins and seeds, such as wine and grape juice, are natural sources of flavonoids in the diet. Carcinogenesis is a multistep process that is characterized by genetic, epigenetic, and phenotypic changes. With increasing knowledge of these mechanisms, and the conclusion that most cases of cancer are preventable, efforts have focused on identifying the agents with potential anticancer properties. The use of grape polyphenols against the carcinogenesis process seems to be a suitable alternative for either prevention and/or therapeutic purposes. The aim of this article is to show the molecular data generated from the use of grape polyphenols against carcinogenesis using in vivo and in vitro test systems.
From Resveratrol to Its Derivatives: New Sources of Natural Antioxidant
Shan He*,1 and Xiaojun Yan*,2
1School of Marine Sciences, Ningbo University, Ningbo 315211, China; 2Key Laboratory of Applied Marine Biotechnology (Ningbo
University), Ministry of Education, Ningbo 315211, China
Abstract: Resveratrol, a star natural product from red wine, has attracted increasing attention around the world. In recent years, resveratrol
derivatives (including its oligomers) have shown amazing chemical diversity and biological activities. They have been emerging to
be promising new sources of natural antioxidant. This review summarizes recent finding on antioxidant activities of resveratrol derivatives
and the structure-activity relationship for the first time. Scientific evidences have highlighted their potential as therapeutic agents for
cerebral and cardiovascular diseases. In our opinion, more effort should be devoted to the synthesis of resveratrol oligomers. Based on
the structure-activity relationship, screening for resveratrol derivatives with higher antioxidant
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Castillo-Pichardo L, Rivera-Rivera A, Dharmawardhane S. Potential of grape polyphenols as breast cancer therapeutics. OA Alternative Medicine 2013 Apr 01;1(1):9.
Potential of grape polyphenols as breast cancer therapeutics. OA Alternative Medicine 2013 Apr 01; 1 (1): 9.
L Castillo-Pichardo, A Rivera-Rivera…
Grape and red wine polyphenols have long been purported to have multiple health benefits.
Although convincing clinical data is still lacking, recent experimental studies have
demonstrated the utility of grape polyphenols as anticancer compounds.
Salvestrols: The Link Between Diet
and Cancer?
Neil Williams
BSc (Hons) Herbal Medicine
2007
1
pdf
ANTICANCER RESEARCH 25: 2055-2064 (2005)
Tumor-specificity and Apoptosis-inducing
Activity of Stilbenes and Flavonoids
SHAHEAD ALI CHOWDHURY1, KAORI KISHINO2, RIE SATOH2,
KEN HASHIMOTO2, HIROTAKA KIKUCHI3, HIROFUMI NISHIKAWA3,
YOSHIAKI SHIRATAKI4 and HIROSHI SAKAGAMI2
1Meikai Pharmaco-Medical Laboratory (MPL), 2Department of Dental Pharmacology and
3Department of Endodontics, Meikai University School of Dentistry, Sakado, Saitama;
4Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
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Patrick Holford
http://www.patrickholford.com/index.php/advice/betterhealtharticle/396/
What are Salvestrols?
Salvestrols are a group of naturally-occurring plant compounds, discovered in 1998 as a result of the combined research of Professor Dan Burke, a pharmacologist, and Professor Gerry Potter, Professor of Medicinal Chemistry and Director of the Cancer Drug Discovery Group at Leicester’s De Montfort University. Potter had spent almost 20 years designing synthetic cancer drugs but realised along the way that plants have similar chemicals   and started to look for natural anticancer remedies.
The science behind Salvestrols started with Potter’s work on resveratrol (an antioxidant chemical found in grape skins and red wine), which is widely credited with cancer preventative properties. It was found that resveratrol is changed by an enzyme, present in both pre-cancerous and cancerous cells, to produce a toxic substance which brings about ‘cell death’ (apoptosis) and therefore destroys the cancer cells. This substance is called piceatannol (pronounced piss-see-at-inol), known to be highly toxic to cancer cells.2 Since Salvestrols are highly selective and only active in cancer cells, they are non-toxic to other cells. Potter developed a drug to mimic the role of resveratrol in fighting cancer, which is currently going through clinical trials.
In the meantime, Potter and his team have been busy analysing many kinds of food and have discovered that there are dozens of natural molecules similar to resveratrol, found in common foods and plants, some of which have an even stronger anticancer activity than resveratrol. Salvestrol is a new name Potter coined to describe this group of natural compounds from the Latin word salve, meaning ‘to save’. The formal definition of a Salvestrol is “a natural dietary anticancer prodrug”.
Gerry Potter Slide presentation
http://www.slideshare.net/gerrypotter52/breakthroughs-in-the-quest-to-cure-cancer
slide show on salvestrols dr gerry potter
CancerCompass Message Baord
http://www.cancercompass.com/message-board/message/all,50825,9.htm
Zyflamend is a blend of 10 herbs. Some of these herbs are rich in the most powerful salvestrols (such as holy basil, rosemary, ginger and oregano) and will compliment salvestrol therapy. In fact some of the herbs in Zyflamend are used in traditional chinese medicine for treating cancer such as scullcap. Zyflamend is completely compatible with salvestrols and they should work well together.
Dear Fernando, I have also heard about positive effects of Saw Palmeto for people with prostate cancer and it probably also contains salvestrols.
Salvestrols, Zyflamend, and Saw Palmeto are all perfectly compatible and should complement one another.
The salvestrol cream was specially formulated to treat basal cell carcinoma and melanoma. It is also usefull for rubbing into areas where there are solid lumps near the skin surface. This cream is super concentrated in salvestrols and has a good local effect.
Each 1000 points contains the equivalent of 10 kilograms of organic food.
RE: Salvestrol by gerrypotter on Mon Apr 09, 2012 10:31 AM
Hi Jennette,Thank you for telling me about your story and a journey that led you to John of God. Fortunately I see God everywhere in the whole creation so I dont have to go to Brazil I can just sit in my garden like today.Salvestrols and Vitamin C are completely compatible and actually help one another in their overall actions.
Milk thistle is a great herb as are all the thistle family including artichoke which is a giant thistle head. These herbs have the highest levels of salvestrol Q40 which clears the liver of metastases so is powerful liver tonic.
Salvestrol Platinum contains 4 salvestrols which are salvestrol Q40, salvestrol T31G, salvestrol T55 and salvestrol Q66. Salvestrol Q40 is the main component and this has the greatest anticancer activity. Salvestrol T31G also has high anticancer activity and has greater bioavailability and is able to cross the blood/brain barrier to target brain tumours and brain metastases. Salvestrols T55 and Q66 can also target brain tumours and also help to boost the levels of the CYP1B1 enzyme that metabolises the salvestrols.
I have encountered 2 cases of people taking salvestrols for oesophageal cancer. One of them responded well to a dose of 2000 points daily, and the other who was a close friend of mine did not respond at all to salvestrols, and the condition continued to worsen and he died following surgery to remove the tumour.
Glioblastoma Multiforme Malignant Brain Tumor
http://www.cancercompass.com/message-board/message/all,50825,23.htm
The problem with treatments for GBM and other forms of brain cancer is getting the drug across the blood brain barrier. Very few molecules can do this which is why temozalomide is one of the few drugs used to treat GBM. This is why we were excited to discover salvestrol T31G which passes the blood brain barrier and was very active against brain tumour cells in the laboratory. We have formulated this in to salvestrol platinum which is why I think it should work against Glioblastoma Multiforme.
I’ve done some background research on the expression of the enzyme CYP1B1 in glioblastomas. Basically the CYP1B1 enzyme is needed to activate the salvestrols, so if its present the salvestrols will work and if it is absent then the salvestrols will not work. Researchers at the MD Anderson Institute in the USA have found that CYP1B1 is present in 81% of glioblastomas. This means that salvestrols will have an 81% chance of working so its well worth giving them a try, Gerry
Indoles are interesting and also empower the salvestrols. They induce the CYP1B1 enzyme activity needed to metabolize salvestrols. The typical indoles are indole-3-carbinol and di-indoylmethane (DIM) and these can be obtained from supplements based on extracts of cruciferous vegetables. If you combined indoles with salvestrols and tamoxifen you could get an even better effect.
http://goarticles.com/search/?type=&q=salvestrol&x=0&y=0
articles on Salvestrols by Gerry Potter
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http://www.cancercompass.com/message-board/message/all,71681,2.htm?mid=522269
Case Report : Esophageal cancer case responds to salvestrols
http://sohumone.com/?page_id=10
Case Report :Prostate cancer metastatic responds to salvestrols
HANS (Health Action Network Society)
Info on Salvestrol®, HANS – to contact by phone (604) 435-0512 (Burnaby, B.C.)
Salvestrol® sales – 1-866-837-1523 (toll free) or (250) 483-3640 (local in Victoria, B.C. Canada)
Brian Schaefer Case Studies
http://www.salvestrolen.nl/ResearchItem.asp?IDResearch=43
Journal of Orthomolecular Medicine artikel: Nutrition and Cancer: Salvestrol Case Studies Brian A Schaefer1 D.Phil. Hoon L. Tan2 Ph.D. MRSC M. Danny Burke3 Ph.D. Gerard A. Potter4 Ph.D.
1    Corresponding author: Clinical Intelligence Corp., 205-1095 McKenzie Avenue, Victoria, BC Canada V8P 2L5; email: bschaefer@aiinc.ca; Tel: 250- 483-3640
2     Director and Medicinal Chemist, Nature’s Defence Investments, Charnwood Science Centre, High Street, Syston, Leicester LE7 1GQ United Kingdom.
3     Professor Emeritus of Pharmaceutical Metabolism, Nature’s Defence Investments. 4     Professor, Head of Cancer Drug Discovery Group, De Montfort University, Leicester LE1 9BH United Kingdom.
News Article:
http://www.thisisleicestershire.co.uk/Private-hell-Leicester-scientist-searching-cancer-wonder-drug/story-12084144-detail/story.html#axzz2VR5NE8Sg
Private hell of Leicester scientist searching for cancer wonder drug

warmest regards,

Jeffrey Dach MD

Offices of Willow Grove

7450 Griffin Road, Suite 190

Davie, Fl 33314

telephone 954-792-4663

Nature’s Sunshine Online Ordering

Pure Caps Supplements Refills Online

Salvestrols, Part Two by Jeffrey Dach MD This article is part two of a series. Click Here for part one.
In part two, we will delve into more detail concerning the biochemistry and molecular biology of Salvestrols based on studies in the medical literature.
Left image courtesy of Dr Kwon in J Nutr Biochem. 2012 (9) Piceatannol inhibits lung mets after injection of prostate cancer cells into mice. Upper row:control animals. Lower row : highest dose of picetannol shows less uptake indicating inhibition of metastatic disease.(9)
In 2000, a Japanese research group discovered that a plant extract found to inhibit a mouse model of lung cancer was actually the compond Piceatannol, a naturally occurring polyphenol present in rhubarb, berries, peanuts, sugar cane, wine and the skins of grapes(1)
Active Ingredient in Salvestrols is Piceatannol – via conversion by the CYP1B1
In 2002, Drs Gerald Potter and Dan Burke reported this same anti-cancer compound, Piceatannol, is a close cousin to Resveratrol.(2) Their 2002 paper in the British Journal of Cancer describes how the CYP 1B1 enzyme present in most cancer cells converts Resveratrol to Piceatannol via hydroxylation at the 4 position of the aromatic ring.(2) They theorized that the CYP1B1 enzyme in tumors may be functioning as a growth suppressor enzyme. (2) The cytochrome enzyme, CYP1B1, is overexpressed in cancer cells and is absent in normal healthy cells. (2)

In 2004, Dr. Larrosa et al found that this same compound, Piceatannol,(left image) is a potent inducer of cell death in human malignant melanoma cancer cells in vitro. (3)
Left Image: Piceatannol chemical structure courtesy of wikimedia commons.
In 2009, A Korean research group found that Piceatannol induces G1 cell cycle arrest in human prostate cancer cells in vitro (4) The authors state: “These results indicate that piceatannol induces apoptosis via the activation of the death receptor and mitochondrial-dependent pathways in prostate cancer cells.” (5)

2012- A Flurry of New Studies
In 2012, Dr Morales from Madrid studied the apoptotic effects of piceatannol and Myricetin, naturally occurring polyphenols in red wine, alone or in combination, in two human cell lines: HL-60 (leukemia) and HepG2 (hepatoma). The piceatannol and Myricetin synergistically induced apoptosis in HL-60 leukemia cells but not in HepG2 hepatoma cells suggesting that anticarcinogenic effects depend on the cell line used. (6)
In 2012, Dr Piotrowska from Poland published this comment: “Piceatannol has been found in various plants, including grapes, passion fruit, white tea, and Japanese knotweed. Besides antioxidative effects, piceatannol exhibits potential anticancer properties as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including leukemia, lymphoma; cancers of the breast, prostate, colon and melanoma.“(7)
Activity Against Hepatoma Bearing Mice

Piceatannol inhibits hepatoma

Also in 2012, a mouse model of human liver cancer (hepatoma) from Dr. Kita of Japan showed that Piceatannol inhibited progression of tumor size and weight. (see image at left) (8)
Left image shows reduction in tumor size and tumor weght in hepatoma bearing mice treated with Piceatannol. Courtesy of Dr Kita in Antiproliferative and anti-invasive effect of piceatannol against hepatoma. Tokyo, Japan. (8)

Also in 2012, a Korean research group found that Piceatannol inhibits development of lung mets in a mouse prostate cancer model.. In this study, rat prostate cancer cells were injected into the tail veins of mice. Mice fed piceatannol had significant inhibition of metastases to the lung. (left Image) (9)
Conclusion:
Cancer cells have the CYP 1B1 enzyme which converts Resveratrol to the anti-cancer metabolite Piceatannol, which is also found in a variety of fruits and vegetables. Recent animal studies and in-vitro studies are summarized above showing the potential anti-cancer effects of these natural compounds. Since they are naturally found in the diet, they are not drugs, rather they nutritional supplements with no adverse effects. Unfortunately, as yet, there is no clinical trial data on these compounds. For the present, all we have are the case reports which are summarized in part one of this series.
This article is part two of a series. Click Here for part one.
Articles with Related interest: Iodine for Breast Cancer Prevention and Treatment
Links and References

Piceatannol

2009

2012

2012

8) http://www.ncbi.nlm.nih.gov/pubmed/22496613

Mouse image study !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

warmest regards,

Jeffrey Dach MD

Offices of Willow Grove

7450 Griffin Road, Suite 190

Davie, Fl 33314

telephone 954-792-4663