Possible Liver issues in extremely high (1500 mg per kg) doses:
doi:10.1016/j.fct.2009.10.030
Copyright © 2009 Elsevier Ltd All rights reserved.
Hepatotoxicity of high oral dose (−)-epigallocatechin-3-gallate in mice
purchase
Joshua D. Lamberta, 
, 
, Mary J. Kennettb, Shengmin Sangc, Kenneth R. Reuhld, Jihyeung Jue, 1 and Chung S. Yange
a Department of Food Science, The Pennsylvania State University, 332 Food Science Building, University Park, PA 16802, USA
b Department of Veterinary Sciences, The Pennsylvania State University, University Park, PA 16802, USA
c Human Nutrition Program, Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, NC 28081, USA
d Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
e Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
Received 20 May 2009;
accepted 25 October 2009.
Available online 31 October 2009.
Abstract
The tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) has been studied for chronic disease preventive effects, and is marketed as part of many dietary supplements. However, case-reports have associated the use of green tea-based supplements with liver toxicity. We studied the hepatotoxic effects of high dose EGCG in male CF-1 mice.
A single dose of EGCG (1500 mg/kg, i.g.) increased plasma alanine aminotransferase (ALT) by 138-fold and reduced survival by 85%. Once-daily dosing with EGCG increased hepatotoxic response. Plasma ALT levels were increased 184-fold following two once-daily doses of 750 mg/kg,
i.g. EGCG. Moderate to severe hepatic necrosis was observed following treatment with EGCG. EGCG hepatotoxicity was associated with oxidative stress including increased hepatic lipid peroxidation (5-fold increase), plasma 8-isoprostane (9.5-fold increase) and increased hepatic metallothionein and γ-histone 2AX protein expression. EGCG also increased plasma interleukin-6 and monocyte chemoattractant protein-1. Our results indicate that
higher bolus doses of EGCG are hepatotoxic to mice. Further studies on the dose-dependent hepatotoxic effects of EGCG and the underlying mechanisms are important given the increasing use of green tea dietary supplements, which may deliver much higher plasma and tissue concentrations of EGCG than tea beverages.
In Vivo. 2005 Jan-Feb;19(1):179-83.
In vivo antitumor effect of ascorbic acid, lysine, proline and green tea extract on human prostate cancer PC-3 xenografts in nude mice: evaluation of tumor growth and immunohistochemistry.
Roomi MW,
Ivanov V,
Kalinovsky T,
Niedzwiecki A,
Rath M.
Matthias Rath Research, Cancer Division, Santa Clara, CA 95050, USA.
BACKGROUND: Matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), Ki 67 (proliferative protein) and constituents of ECM play a critical role in angiogenesis, and are crucial in neoplastic invasion and metastasis. Based on the antitumor properties of certain nutrients, we investigated the effect of a diet containing lysine, proline, arginine, ascorbic acid and green tea extract on the growth of tumors induced by implanting human prostate cancer PC-3 cells in athymic nude mice and on the expression of MMPs, VEGF, Ki 67 and fibronectin in these tumors, as well as the production of mucin (by PAS staining). MATERIALS AND METHODS: Male nude mice (n =12) were inoculated with 3x10(6) prostate cancer PC-3 cells and randomly divided into two groups; Group A was fed a regular diet and Group B was fed a regular diet supplemented with 0.5% of the nutrient mixture (NM). Four weeks later, tumors were excised, weighed and processed for histology. RESULTS: The results showed inhibition of tumor growth in Group B. Histological studies revealed inhibition of MMP-9 and VEGF secretion and mitosis in Group B tissues. CONCLUSION:
Nutrient supplementation strongly suppressed the growth of tumors without any adverse effects in nude mice, suggesting strong potential as an anticancer agent.
PMID: 15796171 [PubMed - indexed for MEDLINE]
Invest New Drugs. 2009 Nov 20. [Epub ahead of print]
Inhibitory effects of tea polyphenols by targeting cyclooxygenase-2 through regulation of nuclear factor kappa B, Akt and p53 in rat mammary tumors.
Roy P,
George J,
Srivastava S,
Tyagi S,
Shukla Y.
Proteomics Laboratory, Indian Institute of Toxicology Research, CSIR, Mahatma Gandhi Marg, Lucknow, 226001, India.
Breast cancer has become the second leading cause of cancer-related deaths worldwide. The control of this disease can be achieved through chemoprevention, which refers to the consumption of synthetic or naturally occurring agents to block, reverse, or delay the process of tumor development. Tea (Camellia sinensis), the most widely consumed beverage, has shown promises in the field of cancer chemoprevention.
Inhibition of tumorigenesis by green or black tea polyphenols has been demonstrated in various in vitro and in vivo models. Here, we examined the inhibitory effect of green tea polyphenol (GTP) and black tea polyphenol (BTP) on the development of mammary tumors- induced by 7, 12-dimethylbenz (a) anthracene (DMBA) in female, Wistar rats. 13% and 33% of animals developed tumors in GTP and BTP supplemented groups, respectively. Both GTP and BTP are effective in significantly inhibiting the cumulative number of mammary tumors (by ~92% and 77%, respectively) and in reducing their growth. Mechanistically, we investigated the effects of GTP and BTP on the components of cell signaling pathways, connecting biomolecules involved in cancer development.
GTP and BTP supplementation as a sole source of drinking solution leads to scavenging of reactive oxygen species (ROS) (by ~72% and 69%, respectively) by inhibiting cyclooxygenase-2 (Cox-2) and inactivation of phosphorylated forms of nuclear factor-kappa B (NF-kappaB) and Akt. Altogether, the study suggests that both cultivars of tea, i.e. green and black, have anti-tumorigenic potential against DMBA-induced mammary tumorigenesis in Wistar rats. Further studies such as large and long term cohort studies and clinical trials are warranted.
PMID: 19936622 [PubMed - as supplied by publisher]
Phytomedicine. 2010 Apr;17(5):356-362. Epub 2010 Feb 10.
(-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line.
Farabegoli F,
Papi A,
Bartolini G,
Ostan R,
Orlandi M.
Department of Experimental Pathology, Via San Giacomo, 14, University of Bologna, 40126 Bologna, Italy.
We investigated the anticancer effect of EGCG treatment on a breast carcinoma cell line resistant to tamoxifen (MCF-7Tam cells). As there are no reports about the molecular mechanisms implicated in EGCG treatment of tamoxifen resistant breast carcinoma cells, we studied the effects of EGCG treatment on three plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein (MRP1), P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). EGCG treatment (10-100mug/ml for 24-72hours) caused cell growth inhibition and dose-dependent apoptosis: after 100mug/ml EGCG treatment for 24hours, Bax expression increased and Bcl2 expression decreased (p<0.05). Coherently, Annexin V-FITC apoptosis assay detected a significant increase in labelled cells (p<0.05). EGCG did not affect MRP1: in contrast, 100mug/ml EGCG administration caused P-gp decrease to 53% of control cells (p<0.001) and this effect was not due to downregulation of P-gp gene expression. EGCG induced P-gp decrease even when MG132, a strong proteasome inhibitor, was given together with EGCG to MCF-7Tam cells. EGCG treatment also inhibited BCRP activity: mRNA transcription and protein level did not change after treatment, but mitoxantrone test demonstrated a strong inhibition of BCRP activity (p<0.001). In conclusion, the present
results showed that EGCG could down-regulate the activity of two molecules that play a key role in drug metabolism and transport and that are highly expressed in tamoxifen resistant breast carcinoma cells. The interaction of EGCG and drugs used in the therapy of estrogen sensitive breast carcinoma ought to be subject of studies and the potential use of EGCG in drug-resistant diseases ought to be better considered. Copyright © 2010 Elsevier GmbH. All rights reserved.
PMID: 20149610 [PubMed - as supplied by publisher]
Epigallocatechin Gallate Dose-Dependently Induces Apoptosis or Necrosis in Human MCF-7 Cells
YAN-DER HSUUW
a AND WEN-HSIUNG CHAN
b a Department of Life Science, National Pingtung University of Science and Technology, Pingtung, Taiwan 912
b Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Chung Li, Taiwan 32023
Address for correspondence: Wen-Hsiung Chan, Department of Bioscience Technology, Chung Yuan Christian University, Chung Li, Taiwan 32023. Voice: +886-3-2653515; fax: +886-3-2653599.
e-mail:
whchan@cycu.edu.tw
Copyright 2007 New York Academy of Sciences
KEYWORDS
catechin . EGCG . apoptosis . necrosis . oxidative stress
ABSTRACT
Abstract : The
catechins, a family of polyphenols found in tea, can evoke various responses, including cell death. However, the precise molecular mechanisms of these effects are unknown. Here, we demonstrate that
treatment of human MCF-7 cells with 50 μM (-)-Epigallocatechin-3-gallate (EGCG), a catechin that is highly abundant in green tea, can induce apoptotic changes, including mitochondrial membrane potential changes and activation of c-Jun N-terminal kinase (JNK), caspase-9, and caspase-3. In contrast, higher concentrations of EGCG (100-400 μM) do not induce apoptosis, but rather trigger necrotic cell death in MCF-7 cells. Investigations of the possible mechanisms underlying these differences revealed that
treatment with lower concentrations of EGCG (10-50 μM) directly increased intracellular oxidative stress, while higher concentrations (100-400 μM) did not. Immunoblotting revealed that treatment of MCF-7 cells with 10-50 μM EGCG caused increases in Bax protein levels and decreases in Bcl-2 protein levels, shifting the Bax-Bcl-2 ratio to favor apoptosis, while treatment with 100-400 μM EGCG had no such effect. Moreover, we observed a dose-dependent decrease in intracellular ATP levels in cells treated with high-dose EGCG. Blockade of reactive oxygen species (ROS) generation and ATP synthesis using antioxidants and ATP synthesis inhibitors revealed that ROS and ATP play important roles to switch cell death types with apoptosis or necrosis. Collectively, these results indicate for the first time that
EGCG treatment has a dose-dependent effect on ROS generation and intracellular ATP levels in MCF-7 cells, leading to either apoptosis or necrosis, and that the apoptotic cascade involves JNK activation, Bax expression, mitochondrial membrane potential changes, and activation of caspase-9 and caspase-3.
DIGITAL OBJECT IDENTIFIER (DOI)
10.1196/annals.1397.046
About DOI
Acta Biochim Biophys Sin (Shanghai). 2009 Dec 15;41(12):1018-26.
Potentiation of (-)-epigallocatechin-3-gallate-induced apoptosis by bortezomib in multiple myeloma cells.
Wang Q,
Li J,
Gu J,
Huang B,
Zhao Y,
Zheng D,
Ding Y,
Zeng L.
Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
The green tea constituent, (-)-epigallocatechin-3-gallate (EGCG), has chemopreventive and anticancer effects. This is partially because of the selective ability of EGCG to induce apoptosis and death in cancer cells without affecting normal cells. In the present study, the activity of EGCG against the myeloma cell line, KM3, was examined. Our results demonstrated, for the first time, that the treatment of the KM3 cell line with EGCG inhibits cell proliferation and induces apoptosis, and there is a synergistic effect when EGCG and bortezomib are combined. Further experiments showed that this effect involves the NF-kappaB pathway. EGCG inhibits the expression of the P65 mRNA and P65/pP65 protein, meanwhile it downregulates pIkappaBalpha expression and upregulates IkappaBalpha expression. EGCG also activates caspase-3, -8, cleaved caspase-9, and poly-ADP-ribose polymerase (PARP) and subsequent apoptosis. These findings provided experimental evidence for efficacy of EGCG alone or in combination with bortezomib in multiple myeloma therapy.
PMID: 20011976 [PubMed - in process]
Cancer Sci.. [Epub ahead of print]
(-)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein.
Luo KL,
Luo JH,
Yu YP.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
(-)-
Epigallocatechin-3-gallate (EGCG) is one of the major polyphenol components in green tea. It effectively induces apoptosis in prostate cancer cells. The anticancer effect of this reagent is appealing because it is a natural component of a popular daily beverage that has proven harmless for thousands of years, making it a good candidate chemopreventive agent. EGCG suppresses cell growth and causes cell death, but the mechanisms are not well characterized, especially in androgen-independent prostate cancer cells. In the present study, using Affymetrix genechip Hu133 2.0, we analyzed the gene expression patterns of the androgen-independent prostate cancer cell line Du145, treated with or without EGCG, and found 40 genes whose expression levels were altered (>twofold, either upregulated or downregulated, P < 0.01) upon treatment with EGCG. These gene products are involved in the functions of transcription, RNA processing, protein folding, phosphorylation, protein degradation, cell motility, and ion transport. Among them,
inhibitor of DNA binding 2 (ID2), known as a dominant anti-retinoblastoma (Rb) helix-loop-helix protein, was found to be downregulated fourfold by EGCG treatment. Forced expression of ID2 in Du145 cells reduced apoptosis and increased cell survival in the presence of EGCG, and knockdown ID2 expression in Du145 cells using a morpholino oligonucleotide specific for ID2 mimicked the apoptosis effect generated by EGCG treatment, although it was milder. To our knowledge, this is the first report indicating that ID2 is one of the critical factors in the signaling pathway of Du145 cell death induced by EGCG. (Cancer Sci 2009).
PMID: 20002680 [PubMed - as supplied by publisher]
Breast Cancer, Chemotherapy, & Antioxidants
BY JOHANNA ALTGELT & MICHAEL McCULLOCH
INTRODUCTION
LINK
Quote:
Green Tea Polyphenols
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.
In a laboratory study from China, it was demonstrated that green tea polyphenol improved effectiveness of Adriamycin in estrogen receptor-positive breast cancer cells that had become resistant to adriamycin treatment (Zhu and Wang, 2001).
» Green Tea Polyphenols (EGCG): One cup of green tea contains between 10 and 400 mg of polyphenols depending on the source, amount of leaves used, and time the tea steeps. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.
|
J Diet Suppl. 2008 Nov 1;5(3):248-263.
Pharmacokinetics of Green Tea Catechins in Extract and Sustained-Release Preparations.
Janle EM,
Morré DM,
Morré DJ,
Zhou Q,
Zhu Y.
Botanical Center In Vivo Core, Purdue University, Department of Foods and Nutrition, West Lafayette, IN.
Catechins are a major constituent of green tea.
For green tea to have cancer therapeutic benefit, catechin concentrations in the range of 100 nM are required continuously until apoptosis (programmed cell death) is induced. To prolong elevated plasma and interstitial concentrations of catechins, a sustained-release formulation of green tea extract was tested and compared to a commercial green tea extract (Tegreen97((R))). Sustained-release formulations are usually developed in the pharmaceutical industry to slowly deliver the compound over a period of time and increase the dosing interval. Plasma and interstitial fluid (ISF) pharmacokinetics of catechins were determined following an oral dose in the rat.
The sustained-release formulation profile included multiple smaller peaks of total catechins in both plasma and ISF. Interstitial fluid profiles of green tea extract indicate that higher catechins concentration and longer duration in tissue than in blood may make a sustained-release form unnecessary.
PMID: 19885387 [PubMed]
Tegreen alternative formula
http://www.nuskin.com/nuskin/us/en/p.../01003529.html
Rasberry seed formulation proposed as higher potency form of EGCG:
http://www.ellagic.net/ellagic-acid-fraud.html
beware of the claims of percentage Ellagic Acid content. It is only the Ellagitannin content that is relevant.
"
The Ellagic Acid compound is much stronger and biologically active then the tannins found in green teas."
J Cell Mol Med. 2008 Nov 6. [Epub ahead of print]
Synergistic promotion of breast cancer cells death by targeting molecular chaperone GRP78 and heat shock protein 70.
Li M,
Wang J,
Jin J,
Hua H,
Luo T,
Xu L,
Wang R,
Liu D,
Jiang Y.
Division of Signal Transduction and Molecular Targeting Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Abstract Heat shock protein 70 (HSP70) is frequently overexpressed in a variety of human malignancies and protects cancer cells against apoptosis in response to various stresses. The bioflavonoid quercetin inhibits HSP70 expression and induces cancer cells apoptosis. In the present study, we investigated the effects of HSP70 down-regulation on the unfolded protein response and addressed a novel strategy to enhance the proapoptotic effect of quercetin by suppressing GRP78 induction simultaneously. Treatment of human breast cancer cells with quercetin down-regulates HSP70 expression, but up-regulates GRP78 expression in a dose-dependent manner. Down-regulation of HSP70 by small interfering RNA also leads to induction of GRP78. Moreover, our studies reveal that HSP70 knockdown or quercetin induces other typical components of the unfolded protein response, including CHOP expression, eIF2a and JNK phosphorylation, caspases activation, and XBP-1 splicing. Abrogating the induction of pro-survival chaperone GRP78 by small interfering RNA sensitizes breast cancer cells to quercetin. Colony survival assays demonstrate that
treatment of breast cancer cells with green tea (-)-epigallocatechin gallate (EGCG), which binds to the ATP-binding domain of GRP78 and blocks its protective function, synergistically promoted quercetin-induced cell death. These studies reveal that HSP70 downregulation leads to the induction of unfolded protein response. The pro-survival GRP78 induction contributes to quercetin resistance. Abrogation of GRP78 induction or inhibition of GRP78 activity increases the effectiveness of quercetin. These
findings indicate that combinational administration of flavonoids capable of suppressing HSP70 and GRP78 such as quercetin and EGCG might represent a novel approach for cancer therapy or chemoprevention.
PMID: 19017364 [PubMed - as supplied by publisher]
- Int J Oncol. 2007 Apr;30(4):963-9.
Links
- Combined effect of green tea and Ganoderma lucidum on invasive behavior of breast cancer cells.
Thyagarajan A, Zhu J, Sliva D.
Cancer Research Laboratory, Methodist Research Institute, E504, Indianapolis, IN 46202, USA.
Epidemiological studies have suggested that consumption of green tea may decrease the risk of a variety of cancers. In addition, mushroom Ganoderma lucidum has been used for the promotion of health, longevity and treatment of cancer in traditional Chinese medicine. In the present study we show that extract from green tea (GTE) increased the anticancer effect of G. lucidum extract (GLE) on cell proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of breast cancer cells. This effect was mediated by the down-regulation of expression of oncogene c-myc in MDA-MB-231 cells. Although individual GTE and GLE independently inhibited adhesion, migration and invasion of MDA-MB-231 cells, their combination demonstrated a synergistic effect, which was mediated by the suppression of secretion of urokinase plasminogen activator (uPA) from breast cancer cells. Our study suggests the potential use of combined green tea and G. lucidum extracts for the suppression of growth and invasiveness of metastatic breast cancers.
Green Tea treatment and links:
http://www.nutraingredients.com/Rese...-tea-treatment
http://www.defense.gov/transformation/articles/2006-05/ta050306a.html
Researchers Discover Possible Anti-Cancer Treatment Researchers at the U.S. Army Natick Soldier Center and the University of
Massachusetts-Lowell unexpectedly discovered a potential anti-cancer treatment.
The effectiveness that is being shown is "incredible" according to
Dr. Ferdinando Bruno, research chemist, Natick Soldier Center
"
The catechin oligomer compounds have been shown to be effective in killing breast, stomach and neck cancer cells, in tissue culture, with approximately 90, 75 and 50 percent inhibition, respectively." Dr. Ferdinando Bruno, research chemist
Dr. Lynne Samuelson, a research chemist from Natick Soldier Center and a pioneer of enzymatic template polymerization, suggested increasing the water solubility of these novel compounds by tethering them to a large molecule called polystyrene sulfonate.
This templated reaction made the naturally occurring catechin oligomer longer lived and more water soluble, but
the modified compound was still not effective against cancer cells at doses that could be administered to humans.
Jayant Kumar, director of the Center for Advanced Materials at University of Massachusetts -Lowell, then suggested
adding ethanol, an alcohol, to try to make the compound more efficient. While growing up, Bruno attended Jesuit schools in Italy.
He remembered the fountains in the schools' cafeterias filled with both water and wine and
suggested adding 10 percent ethanol to the solution, which appears to be the correct combination.
This was a key to the development of the new anti-carcinogens and made these new compounds effective at very low doses.
With increased stability and effectiveness, this family of compounds is now being tested for its efficacy against a wide variety of different human cancers by another University of Massachusetts collaborator,
Dr. Susan J. Braunhut, and her team.
http://nsrdec.natick.army.mil/LIBRARY/00-09/R08-86.pdf
Article
Biocatalytically Oligomerized Epicatechin with Potent and Specific Anti-proliferative Activity for Human Breast Cancer Cells
Subhalakshmi Nagarajan 1,6, Ramaswamy Nagarajan 2, Susan J. Braunhut 3,
Ferdinando Bruno 4
,
Donna McIntosh 3, Lynne Samuelson 4 and Jayant Kumar 5,6,*
1 Department of Chemistry, University of Massachusetts, Lowell, USA
2 Department of Plastics Engineering, University of Massachusetts, Lowell, USA
3 Department of Biological Sciences, University of Massachusetts, Lowell, USA
4 U.S Army Natick Soldier Research, Development & Engineering Center, Natick, MA, 01760
5 Department of Physics, University of Massachusetts, Lowell, USA
6 Center for Advanced Materials, University of Massachusetts, Lowell, USA
* Author to whom correspondence should be addressed. E-mail:
Jayant_Kumar@uml.edu.
Received: 18 August 2008; in revised form: 26 September 2008 / Accepted: 7 October 2008 /
Published: 1 November 2008
Abstract: Catechins, naturally occurring flavonoids derived from wine and green tea, are known to exhibit multiple health benefits. Epigallocatechin gallate (EGCG) is one of the most widely investigated catechins, but its efficacy in cancer therapy is still inconsistent and limited. The poor stability of EGCG has contributed to the disparity in the reported anti-cancer activity and other beneficial properties. Here
we report an innovative enzymatic strategy for the oligomerization of catechins (specifically epicatechin) that yields stable, water-soluble oligomerized epicatechins with enhanced and highly specific anti-proliferative activity for human breast cancer cells. This one-pot oxidative oligomerization is carried out in ambient conditions using Horseradish Peroxidase (HRP) as a catalyst yielding water-soluble oligo(epicatechins). The oligomerized epicatechins obtained exhibit excellent growth inhibitory effects against human breast cancer cells with greater specificity towards growth-inhibiting cancer cells as opposed to normal cells, achieving a high therapeutic differential. Our studies indicate that
water-soluble oligomeric epicatechins surpass EGCG in stability, selectivity and efficacy at lower doses.
Search results on researcher:
HERE
her1, her2 and her 3
They synthesized compounds similar to those in curcumin, green tea, soy genistein--compound 2e which they synthesized blocked her1,2, and 3 signalling which the natural compounds couldn't do as effectively
Since these are artificial compounds , a drug co. may get interested in finding out best dose, schedulling, which patients best to target, etc
Chembiochem. 2010 Jan 7. [Epub ahead of print]
Unnatural Polyketide Analogues Selectively Target the HER Signaling Pathway in Human Breast Cancer Cells.
Kwon SJ, Kim MI, Ku B, Coulombel L, Kim JH, Shawky JH, Linhardt RJ, Dordick JS.
Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180 (USA), Fax: (+1) 5182762207.
Receptor tyrosine kinases are critical targets for the regulation of cell survival. Cancer patients with abnormal receptor tyrosine kinases (RTK) tend to have more aggressive disease with poor clinical outcomes. As a result,
human epidermal growth factor receptor kinases, such as EGFR (HER1), HER2, and HER3, represent important therapeutic targets. Several plant polyphenols including the type III polyketide synthase products (genistein, curcumin, resveratrol, and epigallocatechin-3-galate) possess chemopreventive activity, primarily as a result of RTK inhibition. However, only a small fraction of the polyphenolic structural universe has been evaluated. Along these lines, we have developed an in vitro route to the synthesis and subsequent screening of unnatural polyketide analogues with N-acetylcysteamine (SNAc) starter substrates and malonyl-coenzyme A (CoA) and methylmalonyl-CoA as extender substrates. The resulting polyketide analogues possessed a similar structural polyketide backbone (aromatic-2-pyrone) with variable side chains. Screening chalcone synthase (CHS) reaction products against BT-474 cells resulted in identification of several trifluoromethylcinnamoyl-based polyketides that showed strong suppression of the HER2-associated PI3K/AKT signaling pathway, yet did not inhibit the growth of nontransformed MCF-10A breast cells (IC(50)>100 muM). Specifically,
4-trifluoromethylcinnamoyl pyrone (compound 2 e) was highly potent (IC(50)<200 nM) among the test compounds toward proliferation of several breast cancer cell lines. This breadth of activity likely stems from the ability of compound 2 e to inhibit the phosphorylation of HER1, HER2, and HER3. Therefore, these polyketide analogues might prove to be useful drug candidates for potential breast cancer therapy.
PMID: 20058253 [PubMed - as supplied by publisher]
Br J Haematol. 2010 Jan 20. [Epub ahead of print]
Epigallocatechin-3-gallate induces cell death in acute myeloid leukaemia cells and supports all-trans retinoic acid-induced neutrophil differentiation via death-associated protein kinase 2.
Britschgi A,
Simon HU,
Tobler A,
Fey MF,
Tschan MP.
Department of Clinical Research, Experimental Oncology/Haematology, University of Bern, Bern, Switzerland.
Summary Acute promyelocytic
leukaemia (APL) patients are successfully treated with all-trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover,
combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that
EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes.
PMID: 20096012 [PubMed - as supplied by publisher]
Chem Biol Interact. 2010 Mar 24. [Epub ahead of print]
(-)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells.
Shimizu M,
Shirakami Y,
Sakai H,
Yasuda Y,
Kubota M,
Adachi S,
Tsurumi H,
Hara Y,
Moriwaki H.
Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
(-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, inhibits the growth of colorectal cancer cells by inhibiting the activation of various types of receptor tyrosine kinases (RTKs). The RTK vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis induces tumor angiogenesis in colorectal cancer.
This study examined the effects of EGCG on the activity of the VEGF/VEGFR axis and the expression of hypoxia-inducible factor (HIF)-1alpha, which promotes angiogenesis by elevating VEGF levels, in human colorectal cancer cells. Total and phosphorylated (i.e., activated) form (p-VEGFR-2) of VEGFR-2 proteins were overexpressed in a series of human colorectal cancer cell lines. Within 3hours,
EGCG caused a decrease in the expression of HIF-1alpha protein and VEGF, HIF-1alpha, insulin-like growth factor (IGF)-1, IGF-2, epidermal growth factor (EGF), and heregulin mRNAs in SW837 colorectal cancer cells, which express a constitutively activated VEGF/VEGFR axis. A decrease was also observed in the expression of VEGFR-2, p-VEGFR-2, p-IGF-1 receptor, p-ERK, and p-Akt proteins within 6hours after EGCG treatment.
Drinking EGCG significantly inhibited the growth of SW837 xenografts in nude mice, and this was associated with the inhibition of the expression and activation of VEGFR-2. The consumption of EGCG also inhibited activation of ERK and Akt, both of which are downstream signaling molecules of the VEGF/VEGFR axis, and reduced the expression of VEGF mRNA in xenografts. These findings suggest that EGCG may exert, at least in part, growth-inhibitory effects on colorectal cancer cells by inhibiting the activation of the VEGF/VEGFR axis through suppressing the expression of HIF-1alpha and several major growth factors. EGCG may therefore be useful in the chemoprevention and/or treatment of colorectal cancer. Copyright © 2010. Published by Elsevier Ireland Ltd.
PMID: 20346928 [PubMed - as supplied by publisher]
J Surg Res. 2007 Jul;141(1):115-9.
Dietary influence on pancreatic cancer growth by catechin and inositol hexaphosphate.
McMillan B,
Riggs DR,
Jackson BJ,
Cunningham C,
McFadden DW.
Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, West Virginia, USA.
Abstract
INTRODUCTION: Pancreatic cancer is an extremely virulent form of cancer with few effective treatments. We hypothesized that, alone and in combination, IP6 and catechin would be effective against pancreatic cancer. MATERIALS AND METHODS: Pancreatic (PANC-1 and MIAPACA) cancer cell lines were cultured and treated with IP6 (0.8 mM/well), catechin (100 microM/well), and the combination of the two. Cell viability was measured by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) at 24, 48, and 72 h. Vascular endothelial growth factor (VEGF) was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate (FITC). RESULTS:
Catechin and inositol hexaphosphate (IP6), two naturally occurring molecules found in green tea and high-fiber foods, respectively, are compounds that have been shown to demonstrate anti-proliferative effects when administered as single therapeutic agents against a number of cancers.The combination of catechin and IP6 significantly inhibited proliferation in the PANC-1 cell line at 24, 48, and 72 h compared to single agents (P < 0.001). Growth of the MIAPACA cell line was inhibited (P < 0.01) by each agent alone, but additive inhibitory effects were not seen. An increase in early apoptosis was attributed to catechin therapy in both cell lines (P < 0.01). The combination of these agents also increased early apoptotic activity when compared to the control (P < 0.001). IP6 reduced VEGF in both cell lines (P < 0.01). In combination, catechin and IP6 amplified VEGF reduction compared to each agent in MIAPACA and control (P < 0.002). CONCLUSIONS: These results, combined with the prevalence of these compounds in safe, naturally occurring foods, make catechin and IP6 attractive therapies for treatment, and possibly in preventative trials, of pancreatic cancer.
PMID: 17574044 [PubMed - indexed for MEDLINE]