Salvestrols, Part Two

Piceatannol_inhibits_migration_and_invasion_of_prostate_cancer_cellsSalvestrols, Part Two

by Jeffrey Dach MD

This article is Part Two of a series.
For Part One, Click Here.
For Part Three, Click Here

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

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)

PiceatannolIn 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

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:

Piceatannol_inhibits_migration_and_invasion_of_prostate_cancer_cellsAlso 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.  The case reports are summarized in part one of this series.Here for part one.

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.

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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 DescriptionResveratrol 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.2Piceatannol 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.4,512) 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.
——————————————————————–201313) 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

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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

4 thoughts on “Salvestrols, Part Two

  1. Hello Dr. Dach, I started a Face Book group for Salvestrols and some of the members are very ill and looking for testimonies. If you have any patients with a good story to tell, can you please send them in our direction. Thank you so much for all you information on Salvestrols!

  2. Dear Dr Dach,

    If you would like my pdf on “Delivery from Cancer” you are more than welcome to received and comment and perhaps make revisions and ideas.

    So far we have treated 464 people advising the value of Salvestrol Platinum but insisting that they do their own evaluation as we are not allowed to state a cure nor prevention of cancer in the UK due to legislation,

    Kind regards,

    Michael

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