Anti-Cancer Activity from Natural Plant Pterostilbenes

Pterostilbene_Metastases-Associated_Protein_1_Tumor_inhibition2Anti-Cancer Activity from Natural Plant Pterostilbenes

by Jeffrey Dach MD

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

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) 

BlueBerries_Pterostilbene_Anticancer_jeffrey_Dach_MDLeft Image Blue Berries courtesy of wikimedia commons.

In 1997, Jang reported in Science  the anti-cancer effects of Resveratrol, present in grapes and blue berries, 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 hydroxylated version of Resveratrol, and Pterostilbene a methoxylated version of Resveratrol have been the focus of a flurry of research showing in-vitro and in- vivo  anti-cancer activity.  Pterostilbene is available at the vitamin store as a food supplement.  This article will explain and summarize some of these studies.
Pterostilbene_Source_naturals

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)

Studies confirmed that Pterostilbene exerts antiproliferative and pro-apoptotic effects in lung, gastric, prostate, colon, breast cancers, chronic myelogenous leukemia and lymphoblastic leukemia.(30)

PterostilbeneNumerous studies have been done on showing anti-cancer effects for 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

Mechanism of action:  Acute Myeloid Leukemia Cells

A 2010  article by Pei-Ching Hsiao studied the anti-cancer effects of pterostilbene treatment of various leukemia cell lines.(30)   Dr Hsiao showed that pterostilbene induced apoptosis in cancer cells vIa mitochondrial pathways, (with activation of caspase system).(30)  Pterostilbene suppressed cell proliferation in various Leukemia cell lines, and induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. Pterostilbene induced cancer cell programmed cell death (apoptosis) through activation of caspases-8-9/-3 (apoptosis cascade), and a mitochondrial pathways.(30)

PTERO Downregulates the PI3K/Akt/mTOR pathway

In 2018, Dr Yu studied the effect of pterostilbene on Mantle Cell Lymphoma cells, finding  attenuation of cancer cell progression by downregulation of the  PI3K/Akt/mTOR pathway.(36)

Breast Cancer

Studies show that Pterostilbene induces apoptosis via the mitochondrial pathway in breast cancer cell lines. See the article by Moon. (28)  Another more recent study by Wang in 2012 showed Pterostilbene induces apoptosis and cell cycle arrest in breast cancer cells.(8) Another study by Alosi on Pterostilbene in Breast Cancer also showed similar findings with apoptosis induced by mitochondrial pathways.(11)

Wnt/b-catenin-signaling pathway – Colon Cancer

Dr Shiby Paul reports in his 2010 study in  Carcinogenesis, pterostilbene from blueberries inhibits the β catenin pathway in colon carcinogenesis.(21)  He reports that pterostilbene reduces the Wnt agonist-induced levels of cyclin D1 and Beta-Catenin in the nucleus.  Pterostilbene inhibits colon tumorigenesis by regulating the Wnt/b-catenin-signaling pathway and the inflammatory responses.(21)

Pterostilbene for HPV Infection and Cervical Cancer

In 2018, Dr Chatterjee studied the effect of Pterostilbene on HPV infected cervical cells.  He reports that:

“HPV infection and cancer progression in cervical cells relies on the expression of the viral E6 oncoprotein which targets p53 for degradation by the ubiquitination proteasome pathway, thus causing uncontrolled cell proliferation….Pterostilebene causes suppression of E6 and upregulation of p53.”(33)

“pterostilbene was superior to resveratrol in suppressing E6 while upregulating p53 and active-caspase-3 expression, thus causing a greater degree of apoptosis-mediated cell elimination.”(33-35)

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.

Addendum Jan 2015:  Pterostilbene Reduces Blood Pressure: Impact Of Pterostilbene On Blood Pressure and Other Metabolic Parameters In Adults  Pterostilbene 125 mg twice a day reduced blood pressure 7-8 mm for men and women.

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

Articles with related interest:

Targeting Cancer Stem Cells with Non-Toxic Therapies

Artemisinin, Anti-Cancer Gift From China

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

2013

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.

 

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

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) 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)
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.
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.

21) Paul, Shiby, et al. “Dietary intake of pterostilbene, a constituent of blueberries, inhibits the β-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats.” Carcinogenesis 31.7 (2010): 1272-1278.pterostilbene blueberries inhibits the β catenin pathway in colon carcinogenesis Paul Shiby 2010

pterostilbene downregulated the expression of b-catenin and cyclin D1 targets of WNT pathway.  pterostilbene reduced the Wnt agonist-induced levels of cyclin D1 and b-catenin in the nucleus.  pterostilbene inhibits colon tumorigenesis by regulating the Wnt/b-catenin-signaling pathway and the inflammatory responses.

22) Pan MH, Chiou YS, Chen WJ, Wang JM, Badmaev V, Ho CT. Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Carcinogenesis. 2009;30:1234–1242. [PubMed]

23) Chiou YS, Tsai ML, Wang YJ, Cheng AC, Lai WM, Badmaev V, Ho CT, Pan MH. Pterostilbene inhibits colorectal aberrant crypt foci (ACF) and colon carcinogenesis via suppression of multiple signal transduction pathways in azoxyme-thane-treated mice. J Agric Food Chem. 2010;58:8833–8841. [PubMed]

24) Schneider JG, Alosi JA, McDonald DE, McFadden DW. Pterostilbene inhibits lung cancer through induction of apoptosis. J Surg Res. 2010;161:18–22. [PubMed]

25) Alosi JA, McDonald DE, Schneider JS, Privette AR, McFadden DW. Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis. J Surg Res. 2010;161:195–201. [PubMed]

26) Mannal PW, Alosi JA, Schneider JG, McDonald DE, McFadden DW. Pterostilbene inhibits pancreatic cancer in vitro. J Gastrointest Surg. 2010;14:873–879. [PubMed]

27) Pan MH, Chang YH, Badmaev V, Nagabhushanam K, Ho CT. Pterostilbene induces apoptosis and cell cycle arrest in human gastric carcinoma cells. J Agric Food Chem. 2007;55:7777–7785. [PubMed]

28) Moon, D., et al. “Pterostilbene Induces Mitochondrially-Derived Apoptosis in Breast Cancer in Vitro Via Bax Activation and Cytosolic Calcium Overload.” Journal of Surgical Research 172.2 (2012): 342.
pterostilbene has an anti-proliferative effect and induces apoptosis in breast cancer cells in vitro via Bax activation and overexpression,

29) McCormack, Denise E., Debbie E. McDonald, and David W. McFadden. “Pterostilbene Induces Mitochondrially-Derived Apoptosis in Pancreatic Cancer Cells by Increasing MnSOD Activity and Release of Cytochrome C and Smac/DIABLO.” Gastroenterology 140.5 (2011): S-1026.

Various AML Cell Lines – Acute Myelogenous Leukema

30) Hsiao, Pei-Ching, et al. “Pterostilbene simultaneously induced G0/G1-phase arrest and MAPK-mediated mitochondrial-derived apoptosis in human acute myeloid leukemia cell lines.” PloS one 9.8 (2014): e105342.

PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway.

31)  Dhar, Swati, et al. “Dietary pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer.” Oncotarget 7.14 (2016): 18469.
Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.

32)  Ann N Y Acad Sci. 2017 Sep;1403(1):15-26. doi: 10.1111/nyas.13372. Epub 2017 Jun 29. Resveratrol and pterostilbene as a microRNA-mediated chemopreventive and therapeutic strategy in prostate cancer.
Kumar A1, Rimando AM2, Levenson AS1.
Growing evidence indicates that deregulation of the epigenetic machinery comprising the microRNA (miRNA) network is a critical factor in the progression of various diseases, including cancer. Concurrently, dietary phytochemicals are being intensively studied for their miRNA-mediated health-beneficial properties, such as anti-inflammatory, cardioprotective, antioxidative, and anticancer properties. Available experimental data have suggested that dietary polyphenols may be effective miRNA-modulating chemopreventive and therapeutic agents. Moreover, noninvasive detection of changes in miRNA expression in liquid biopsies opens enormous possibilities for their clinical utilization as novel prognostic and predictive biomarkers. In our published studies, we identified resveratrol-regulated miRNA profiles in prostate cancer. Resveratrol downregulated the phosphatase and tensin homolog (PTEN)-targeting members of the oncogenic miR-17 family of miRNAs, which are overexpressed in prostate cancer. We have functionally validated the miRNA-mediated ability of resveratrol and its potent analog pterostilbene to rescue the tumor suppressor activity of PTEN in vitro and in vivo. Taken together, our findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.

Pterostilebene and HPV – E6

33) Chatterjee, Kaushiki, et al. “Resveratrol and Pterostilbene Exhibit Anticancer Properties Involving the `Downregulation of HPV Oncoprotein E6 in Cervical Cancer Cells.” Nutrients 10.2 (2018): 243.

Cervical cancer is one of the most common cancers in women living in developing countries. Due to a lack of affordable effective therapy, research into alternative anticancer compounds with low toxicity such as dietary polyphenols has continued. Our aim is to determine whether two structurally similar plant polyphenols, resveratrol and pterostilbene, exhibit anticancer and anti-HPV (Human papillomavirus) activity against cervical cancer cells. To determine anticancer activity, extensive in vitro analyses were performed. Anti-HPV activity, through measuring E6 protein levels, subsequent downstream p53 effects, and caspase-3 activation, were studied to understand a possible mechanism of action. Both polyphenols are effective agents in targeting cervical cancer cells, having low IC50 values in the µM range. They decrease clonogenic survival, reduce cell migration, arrest cells at the S-phase, and reduce the number of mitotic cells. These findings were significant, with pterostilbene often being more effective than resveratrol. Resveratrol and to a greater extent pterostilbene downregulates the HPV oncoprotein E6, induces caspase-3 activation, and upregulates p53 protein levels. Results point to a mechanism that may involve the downregulation of the HPV E6 oncoprotein, activation of apoptotic pathways, and re-establishment of functional p53 protein, with pterostilbene showing greater efficacy than resveratrol.

Studies on colon cancer cell lines have shown pterostilbene to be more potent than resveratrol in inhibiting DNA synthesis and in decreasing the expression of inflammatory genes responsible for cancer progression

An in silico docking study has shown that resveratrol interacts with the p53 binding site of E6 residues [23]. E6 is a vital HPV oncoprotein essential for cervical cancer progression. E6 binds to tumor suppressor protein p53 and targets it for degradation by the ubiquitin proteasome pathway [24], thus causing uncontrolled cell proliferation.

In addition to being effective at sub-IC50 concentrations, the supra-IC50 concentration of pterostilbene (50 µM) was also superior to resveratrol (at 50 µM) in suppressing E6 while upregulating p53 and active-caspase-3 expression, thus causing a greater degree of apoptosis-mediated cell elimination. This observed suppression of E6 and upregulation of p53 is of paramount importance because HPV infection and cancer progression in cervical cells relies on the expression of the viral E6 oncoprotein which targets p53 for degradation by the ubiquitination [24,31].

Here, we show that pterostilbene potently suppresses HPV E6 expression (Figure 4) and efficiently eliminates HPV+ cells in culture by p53-mediated apoptosis (Figure 1 and Figure 5) while suppressing cell proliferation (Figure 3) and migration (Figure 2). We find that pterostilbene is a more promising agent against cervical cancer when compared to resveratrol. Based on such properties, the use of pterostilbene presents a relatively economical but highly hopeful therapeutic approach to treat HPV infections and cervical cancers.

34) Chatterjee, Kaushiki, et al. “Dietary polyphenols, resveratrol and pterostilbene exhibit antitumor activity on an HPV E6-positive cervical cancer model An in vitro and in vivo analysis.” Frontiers in oncology 9 (2019): 352.

35)  McCubrey, James A., et al. “Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs.” Aging (Albany NY) 9.6 (2017): 1477.

PTERO Downregulates the PI3K/Akt/mTOR pathway

36) Yu, Dandan, et al. “Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.” Acta biochimica et biophysica Sinica 50.8 (2018): 782-792.

Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.

PTE inhibited the PI3K/Akt/mTOR pathway, which may be involved in the antiproliferative mechanism of PTE in MCL cells.

37)  Kong, Yuanyuan, et al. “Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells.” Scientific reports 6 (2016): 37417.

38) Chang, Gaomei, et al. “Pterostilbene induces cell apoptosis and cell cycle arrest in T-cell leukemia/lymphoma by suppressing the ERK1/2 pathway.” BioMed research international 2017 (2017).

39)     118) Dong, J., H. Guo, and Y. Chen. “Pterostilbene induces apoptosis through caspase activation in ovarian cancer cells.” Eur J Gynaecol Oncol 37.3 (2016): 342-7.

40)      119) Chen, Gege, et al. “The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells.” Oncology reports 38.1 (2017): 488-496.

41)   Guo, Liying, et al. “Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis.” Oncology reports 36.6 (2016): 3233-3240.

42)      120) Bin, Wu Hong, et al. “Pterostilbene (3’, 5’-dimethoxy-resveratrol) exerts potent antitumor effects in HeLa human cervical cancer cells via disruption of mitochondrial membrane potential, apoptosis induction and targeting m-TOR/PI3K/Akt signalling pathway.” Journal of BU ON.: official journal of the Balkan Union of Oncology 23.5 (2018): 1384-1389.

43)       121) La Spinaa, Martina, et al. “Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study.” Cell Physiol Biochem 52 (2019): 232-239.

44) Tan, Kok‑Tong, et al. “Pterostilbene inhibits lung squamous cell carcinoma growth in vitro and in vivo by inducing S phase arrest and apoptosis.” Oncology letters 18.2 (2019): 1631-1640.

Pterostilbene and Chloroquin Synergy

45) Papandreou, Ioanna, et al. “Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy.” Experimental cell research 339.1 (2015): 147-153.

We performed a screen of 1726 small, drug like molecules to identify those that could activate an ER-stress responsive luciferase gene. After secondary screening, we determined that the plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group. ER stress can be particularly toxic to cells with high ER load, so we examined their effect on cells expressing the Wnt family of secreted glycoprotein growth factors. Molecular analysis determined that these ER stress-inducing stilbenes could block Wnt processing and also induce autophagy in acute lymphoblastic leukemia cells expressing Wnt16. Combining pterostilbene (to induce ER stress) with chloroquine (to inhibit autophagy) lead to significant cellular toxicity in cells from aggressive acute lymphoblastic leukemia.

CONCLUSIONS:  Plant stilbenes are potent inducers of ER stress. However, their toxicity is more pronounced in cancer cells expressing Wnt growth factors. The toxicity of stilbenes in these ALL cells can be potentiated by the addition of autophagy inhibitors, suggesting a possible therapeutic application.

Pterostilbene is a PPAR agonist (like fenofibrate)

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

Jeffrey Dach MD
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Anti-Cancer Activity from Natural Plant Pterostilbenes
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One thought on “Anti-Cancer Activity from Natural Plant Pterostilbenes

  1. My Wife and I have been eating Salvestrol Platinum 2000 for over ten years. Question, What is the bioavailability of salvestrol. We have been advised by De Montfort University that Resveratrol is merely digested and fails to activate the CYP1B1 protein/enzyme so is a waste of time and money.

    I haven’t been able to elucidate the answer either about pterostilbene.

    We are told that salvestrol from blueberry, blackberry, red grape and bitter orange is suitable becuse of its excellent bioavailabilty. I am not yet convinced so what is the answer please.

    PS We are healthy and as far a we know free of carcinogenisis.

    Thank you for your close attention to this lack of knowledge about bioavailability.

    Cheers and Kind regards to all of your team.

    Michael Cleary (chartered civil and science teacher)

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