DNC News

Dietary Aromatase Inhibitors may be useful in Breast Cancer and curiously also in prostate cancer

Jacob Schor, ND

July 11, 2007


About three quarters of all breast cancers are hormone sensitive that is the tumor cells are stimulated to proliferate by the hormone estrogen. Blocking this stimulation has become a key component in the long-term treatment of these cancers. The FDA first approved the drug Tamoxifen in 1977 and it quickly became the standard of care for treating metastatic breast cancer and in preventing recurrent breast cancer. Tamoxifen works by binding to estrogen receptors and blocking estrogen from being able to attach and stimulate the cancer cells. It is the largest selling breast cancer treatment in the world. Estimates are that five years of tamoxifen therapy reduces mortality from breast cancer by 31%.Tamoxifen does have its down sides: it increases risk of endometrial cancer by 2.4 times and thromboembolitic disease by 1.9 times.



Aromatase inhibiting drugs came on the market about ten years ago for use in the treatment and have recently replaced Tamoxifen as the accepted standard of care in post menopausal breast cancer patients. Tamoxifen continues to be the standard for premenopausal women. Aromatase inhibiting drugs work quite differently than Tamoxifen. The estrogen in menopausal women comes from the adrenal glands rather than the ovaries. The adrenal glands secrete a chemical called androstenedione which is then converted in fatty areas of the body into estrogen. The enzyme that converts the androstenedione is called aromatase. Blocking aromatase provides a means to block estrogen production. The drugs being used as aromatase inhibitors can reduce estrogen production by 90 to 95%.


Although these aromatase inhibiting drugs are much safer than Tamoxifen in general they do seem to cause more symptomatic complaints than Tamoxifen does. The most common complaint we have seen in patients is arthralgia, that is joint pain. They start taking the drug and wake up feeling stiff like they developed arthritis almost overnight.


The symptoms can be severe enough that some patients refuse to continue treatment with aromatase inhibitors. As much as these drugs provide long term benefit in treating cancer, these patients can not tolerate the short term discomfort. We may soon be able to offer them another option for consideration.


Dr. Shiuan Chen at the City of Hope in Duarte , California has been steadily publishing research over the last half dozen years on dietary aromatase inhibitors. At first, Chen and his research group found that a group of plant chemicals called procyanidin B dimmers, members of the polyphenol family, were aromatase inhibitors. Knowing that grape seeds are a good source of this chemical they ran out to their local health food stores and bought every grape seed product they could fine. They tested the aromatase inhibition action of 13 different brands of grape seed extracts in cell and animal studies and found that ten worked. They published their initial research in December 2003 and reported that grape seed extracts lowered estrogen levels and slowed tumor growth. [i] They confirmed these early findings in greater detail in a Cancer Research published paper in June 2006. [ii] The grape seed extracts that had effect showed at least an 80% inhibition of aromatase.


Chen examined extracts of a number of other foods looking for aromatase inhibition and curiously found that whit button mushrooms were particularly effective. Other mushrooms including shitake, portabello and crimini also had an effect when tested but Chen's efforts have focused on the whit buttons as they are the most available. [iii] [iv]


To this point Chen's team of researchers have been testing their theories in test tubes and animals. They have begun a Phase I human trial using four different doses of grape seed extract. Phase I trials do not look for clinical benefit as much as toxic reactions. Although one would not predict problems with grape seed extract as it has a long history of use, this is how cancer treatments are tested. Phase I to look for toxicity, followed by Phase II trials to narrow down a therapeutically effective dose and the Phase III to measure the clinical benefit of this dose.


The current Phase I trial of grape seed extract is attempting to measure whether it prevents cancer in women with risk factors for developing breast cancer. Doses being tested range from 50 mg to 300 mg per day.


Though a bit off topic, Dr. Chen has reported that in addition to the aromatase inhibition, the mushrooms also suppressed production of the enzyme 5-alpha reductase. This enzyme plays a big role in development of prostate cancer. White button mushrooms when fed to mice prevent development of prostate cancer.


A series of studies have come out of the School of Pharmacy here in Denver suggesting that grape seed extracts can be useful in treating prostate cancer. [v] [vi] [vii]


True, we do not have adequate human data to prove that these therapies work. Yet for the estrogen receptor positive woman who is unable to tolerate standard aromatase inhibitor therapy, grape seed extracts and a diet high in mushrooms is a reasonable alternative. It is unlikely to hurt and might help and probably far better than doing nothing.






[i] Cancer Res. 2003 Dec 1;63(23):8516-22. Click here to read

Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds.

Eng ET , Ye J , Williams D , Phung S , Moore RE , Young MK , Gruntmanis U , Braunstein G , Chen S .

City of Hope Graduate School of Biological Science,Department of Surgical Research, Beckman Research Institute of the City of Hope , Duarte , California 91010 , USA .

In breast cancer, in situ estrogen production has been demonstrated to play a major role in promoting tumor growth. Aromatase is the enzyme responsible for the conversion of androgen substrates into estrogens. This enzyme is highly expressed in breast cancer tissue compared with normal breast tissue. A wine extract fraction was recently isolated from red wine that exhibited a potent inhibitory action on aromatase activity. Using UV absorbance analysis, high-performance liquid chromatography profiling, accurate mass-mass spectrometry, and nanospray tandem mass spectrometry, most of the compounds in our red wine fraction were identified as procyanidin B dimers that were shown to be aromatase inhibitors. These chemicals have been found in high levels in grape seeds. Inhibition kinetic analysis on the most potent procyanidin B dimer has revealed that it competes with the binding of the androgen substrate with a K(i) value of 6 micro M. Because mutations at Asp-309, Ser-378, and His-480 of aromatase significantly affected the binding of the procyanidin B dimer, these active site residues are thought to be important residues that interact with this phytochemical. The in vivo efficacy of procyanidin B dimers was evaluated in an aromatase-transfected MCF-7 breast cancer xenograft model. The procyanidin B dimers were able to reduce androgen-dependent tumor growth, indicating that these chemicals suppress in situ estrogen formation. These in vitro and in vivo studies demonstrated that procyanidin B dimers in red wine and grape seeds could be used as chemopreventive agents against breast cancer by suppressing in situ estrogen biosynthesis.

PMID: 14679019 [PubMed - indexed for MEDLINE]


[ii] Cancer Res. 2006 Jun 1;66(11):5960-7. Click here to read

Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression.

Kijima I , Phung S , Hur G , Kwok SL , Chen S .

Department of Surgical Research, Beckman Research Institute of the City of Hope , Duarte , California , USA .

Aromatase is the enzyme that converts androgen to estrogen. It is expressed at higher levels in breast cancer tissues than normal breast tissues. Grape seed extract (GSE) contains high levels of procyanidin dimers that have been shown in our laboratory to be potent inhibitors of aromatase. In this study, GSE was found to inhibit aromatase activity in a dose-dependent manner and reduce androgen-dependent tumor growth in an aromatase-transfected MCF-7 (MCF-7aro) breast cancer xenograft model, agreeing with our previous findings. We have also examined the effect of GSE on aromatase expression. Reverse transcription-PCR experiments showed that treatment with 60 mug/mL of GSE suppressed the levels of exon I.3-, exon PII-, and exon I.6-containing aromatase mRNAs in MCF-7 and SK-BR-3 cells. The levels of exon I.1-containing mRNA, however, did not change with GSE treatment. Transient transfection experiments with luciferase-aromatase promoter I.3/II or I.4 reporter vectors showed the suppression of the promoter activity in a dose-dependent manner. The GSE treatment also led to the down-regulation of two transcription factors, cyclic AMP-responsive element binding protein-1 (CREB-1) and glucocorticoid receptor (GR). CREB-1 and GR are known to up-regulate aromatase gene expression through promoters I.3/II and I.4, respectively. We believe that these results are exciting in that they show GSE to be potentially useful in the prevention/treatment of hormone-dependent breast cancer through the inhibition of aromatase activity as well as its expression.

PMID: 16740737 [PubMed - indexed fo


[iii] Cancer Res. 2006 Dec 15;66(24):12026-34. Click here to read

Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus).

Chen S , Oh SR , Phung S , Hur G , Ye JJ , Kwok SL , Shrode GE , Belury M , Adams LS , Williams D .

Department of Surgical Research, Beckman Research Institute of the City of Hope , Duarte , California 91010 , USA . schen@coh.org

White button mushrooms (Agaricus bisporous) are a potential breast cancer chemopreventive agent, as they suppress aromatase activity and estrogen biosynthesis. Therefore, we evaluated the activity of mushroom extracts in the estrogen receptor-positive/aromatase-positive MCF-7aro cell line in vitro and in vivo. Mushroom extract decreased testosterone-induced cell proliferation in MCF-7aro cells but had no effect on MCF-10A, a nontumorigenic cell line. Most potent mushroom chemicals are soluble in ethyl acetate. The major active compounds found in the ethyl acetate fraction are unsaturated fatty acids such as linoleic acid, linolenic acid, and conjugated linoleic acid. The interaction of linoleic acid and conjugated linoleic acid with aromatase mutants expressed in Chinese hamster ovary cells showed that these fatty acids inhibit aromatase with similar potency and that mutations at the active site regions affect its interaction with these two fatty acids. Whereas these results suggest that these two compounds bind to the active site of aromatase, the inhibition kinetic analysis indicates that they are noncompetitive inhibitors with respect to androstenedione. Because only conjugated linoleic acid was found to inhibit the testosterone-dependent proliferation of MCF-7aro cells, the physiologically relevant aromatase inhibitors in mushrooms are most likely conjugated linoleic acid and its derivatives. The in vivo action of mushroom chemicals was shown using nude mice injected with MCF-7aro cells. The studies showed that mushroom extract decreased both tumor cell proliferation and tumor weight with no effect on rate of apoptosis. Therefore, our studies illustrate the anticancer activity in vitro and in vivo of mushroom extract and its major fatty acid constituents.

PMID: 17178902 [PubMed - indexed for MEDLINE]


[iv] J Nutr. 2001 Dec;131(12):3288-93. Click here to read

White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation.

Grube BJ , Eng ET , Kao YC , Kwon A , Chen S .

Division of Immunology, Beckman Research Institute of the City of Hope , Duarte , CA 91010 , USA .

Estrogen is a major factor in the development of breast cancer. In situ estrogen production by aromatase/estrogen synthetase in breast cancer plays a dominant role in tumor proliferation. Because natural compounds such as flavones and isoflavones have been shown to be inhibitors of aromatase, it is thought that vegetables that contain these phytochemicals can inhibit aromatase activity and suppress breast cancer cell proliferation. Heat-stable extracts were prepared from vegetables and screened for their ability to inhibit aromatase activity in a human placental microsome assay. The white button mushroom (species Agaricus bisporus) suppressed aromatase activity dose dependently. Enzyme kinetics demonstrated mixed inhibition, suggesting the presence of multiple inhibitors or more than one inhibitory mechanism. "In cell" aromatase activity and cell proliferation were measured using MCF-7aro, an aromatase-transfected breast cancer cell line. Phytochemicals in the mushroom aqueous extract inhibited aromatase activity and proliferation of MCF-7aro cells. These results suggest that diets high in mushrooms may modulate the aromatase activity and function in chemoprevention in postmenopausal women by reducing the in situ production of estrogen.

PMID: 11739882 [PubMed - indexed for MEDLINE]


[v] Carcinogenesis. 2002 Nov;23(11):1869-76. Links

Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release.

Agarwal C , Singh RP , Agarwal R .

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver , CO 80262 , USA . Chapla.Agarwal@UCHSC.edu

Grape seed extract (GSE), rich in the bioflavonoids commonly known as procyanidins, is one of the most commonly consumed dietary supplements in the United States because of its several health benefits. Epidemiological studies show that many prostate cancer (PCA) patients use herbal extracts as dietary supplements in addition to their prescription drugs. Accordingly, in recent years, we have focused our attention on assessing the efficacy of GSE against PCA. Our studies showed that GSE inhibits growth and induces apoptotic death of human PCA cells in culture and in nude mice. Here, we performed detailed studies to define the molecular mechanism of GSE-induced apoptosis in advanced human PCA DU145 cells. GSE treatment of cells at various doses (50-200 micro g/ml) for 12-72 h resulted in a moderate to strong apoptotic death in a dose- and time-dependent manner. In the studies assessing the apoptotic-signaling pathway induced by GSE, we observed an increase in cleaved fragments of caspases 3, 7 and 9 as well as PARP in GSE-treated cells after 48 and 72 h of treatment. Pre-treatment of cells with general caspases inhibitor, z-Val-Ala-Asp(OMe)-FMK or caspase 3-like proteases inhibitor [z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-FMK], almost completely (approximately 90%) inhibited the GSE-induced apoptotic cell death. In a later case, GSE-induced caspase-3 activity was completely inhibited. Selective caspase 9 inhibitor [z-Leu-Glu(OMe)-His-Asp(OMe)-FMK] showed only partial inhibition of GSE-induced apoptosis whereas GSE-induced protease activity of caspase 9 was completely inhibited. Upstream of caspase cascade, GSE showed disappearance of mitochondrial membrane potential and an increase in cytochrome c release in cytosol. Together, these results suggest that GSE possibly causes mitochondrial damage leading to cytochrome c release in cytosol and activation of caspases resulting in PARP cleavage and execution of apoptotic death of human PCA DU145 cells. Furthermore, GSE-caused caspase 3-mediated apoptosis also involves other pathway(s) including caspase 9 activation.

PMID: 12419835 [PubMed - indexed for MEDLINE]


[vi] Int J Cancer. 2004 Feb 20;108(5):733-40. Links

Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3.

Singh RP , Tyagi AK , Dhanalakshmi S , Agarwal R , Agarwal C .

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver , CO 80262 , USA .

Dietary intake of many fruits and vegetables has been shown to be associated with reduced risk of cancer. We investigated the in vivo efficacy of grape seed extract (GSE, patented as Traconol) against prostate cancer (PCA) and associated molecular events. Athymic nude mice were implanted with hormone-refractory human prostate carcinoma DU145 cells and fed with 100 and 200 mg/kg/day (5 days/week) doses of GSE for 7 weeks. At the end of experiment, tumors were immunohistochemically analyzed for cell proliferation, apoptosis and angiogenesis. Our data show that GSE feeding strongly inhibited tumor growth that accounted for 59-73% (p < 0.001) inhibition in tumor volume and 37-47% (p < 0.05) decrease in tumor weight at the end of the experiment. It did not show any significant change in body weight gain profile and diet consumption. Immunohistochemical analysis of tumors showed that GSE decreases proliferation index by 51-66% (p < 0.001) and increases apoptotic index by 3-4-fold (p < 0.001). CD31 staining for endothelial cells, showed decrease in intratumoral microvasculature in GSE-fed group of mice. Control tumors showed 64.0 +/- 1.6 CD31 positive cells/400x field compared to 23.2 +/- 0.9 and 15.7 +/- 0.08 (p < 0.001) CD31 positive cells in 100 and 200 mg/kg doses of GSE-treated tumors, respectively. GSE strongly inhibited (47-70%, p < 0.05) vascular endothelial growth factor (VEGF) secretion in conditioned medium by DU145 cells. Recently, the circulating level of insulin-like growth factor binding protein (IGFBP)-3 is shown to inversely related with PCA risk, growth and prognosis. Consistent with this, we observed 6-7-fold (p < 0.001) increase in tumor-secreted levels of IGFBP-3 after GSE feeding. In other immunohistochemical studies, compared to controls, tumor xenografts from GSE-fed groups of mice showed a moderate decrease in VEGF but an increase in IGFBP-3 levels. These findings suggest that GSE possesses in vivo anticancer efficacy against hormone-refractory human PCA, which is associated with its antiproliferative, proapoptotic and antiangiogenic activities together with upregulation of IGFBP-3. Copyright 2003 Wiley-Liss, Inc.

PMID: 14696100 [PubMed - indexed for MEDLINE]


[vii] Cancer Res. 2007 Jun 15;67(12):5976-82.

Oral grape seed extract inhibits prostate tumor growth and progression in TRAMP mice.

Raina K , Singh RP , Agarwal R , Agarwal C .

Department of Pharmaceutical Sciences, School of Pharmacy , University of Colorado Health Sciences Center , Denver , Colorado 80262 , USA .

Prostate cancer chemoprevention is an alternative and potential strategy to control this malignancy. Herein, we evaluated the chemopreventive efficacy of grape seed extract (GSE) against prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice where animals were fed with GSE by oral gavage at 200 mg/kg body weight dose during 4 to 28 weeks of age. Our results showed a significant reduction (46%, P < 0.01) in the weight of genitourinary tract organs in the GSE-fed mice. The GSE-fed group of mice had a higher incidence of prostatic intraepithelial neoplasia but showed strong reduction in the incidence of adenocarcinoma compared with mice in control group. Prostate tissue from the GSE group showed approximately 50% (P < 0.001) decrease in proliferating cell nuclear antigen (PCNA)-positive cells and 64% (P < 0.01) reduction in total PCNA protein level compared with the control group; however, GSE increased apoptotic cells by 8-fold. Furthermore, GSE strongly decreased the protein levels of cyclin B1, cyclin A, and cyclin E by 84% (P < 0.05), 96% (P < 0.05), and 89% (P < 0.001), respectively. The protein expression of cyclin-dependent kinases 2 and 6 and Cdc2 was also decreased by more than 90% (P < 0.05) in the prostate from the GSE-fed group. Together, for the first time, we identified that oral GSE inhibits prostate cancer growth and progression in TRAMP mice, which could be mediated via a strong suppression of cell cycle progression and cell proliferation and an increase in apoptosis.

PMID: 17575168 [PubMed - in process]


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