Combining Computational and Biochemical Studies for a Rationale on the Anti‐Aromatase Activity of Natural Polyphenols

Neves, Marco A. C.; Dinis, Teresa C.P.; Colombo, Giorgio; Melo, M. L. Sá e

doi:10.1002/cmdc.200700149

Cited by 33 publications

(29 citation statements)

References 32 publications

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“…3). Resveratrol has been shown to interact with protein kinase C, 10 aromatase, 11 hetero-dimeric alphaVbeta3 integrin, 12 multidrug resistance protein 1, 13 β-lactoglubulin, 14 human serum albumin, 15 human DNA topoisomerase II, 16 plasma lipoprotein, 17 nucleic acids, 18 DNA polymerase α and δ, 19 myeloperoxidase, 20 tubulin, 21 estrogen receptor α and β, 22 F1-ATPase, 23 sulfonyl urea receptors, 24 cytosolic alcohol dehydrogenase, 25 amyloid fibrils 26 and dihydronicotinamide riboside quinone reductase 2 (NQO2). 27 In most cases interaction of resveratrol with these proteins leads to inactivation of the molecule.…”

Section: Molecular Targets Of Resveratrolmentioning

confidence: 99%

Resveratrol: A multitargeted agent for age-associated chronic diseases

Harikumar¹,

Aggarwal²

2008

Cell Cycle

481

339

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Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g., NFκB, STAT3, HIF-1α, β-catenin and PPAR-γ), suppress the expression of antiapoptotic gene products (e.g., Bcl-2, Bcl-X L , XIAP and survivin), inhibit protein kinases (e.g., src, PI3K, JNK and AKT), induce antioxidant enzymes (e.g., catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.

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Section: Molecular Targets Of Resveratrolmentioning

confidence: 99%

Resveratrol: A multitargeted agent for age-associated chronic diseases

Harikumar¹,

Aggarwal²

2008

Cell Cycle

481

339

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“…[107], was reported to strongly inhibit aromatase in microsomes [107], to moderately inhibit aromatase in another microsomal test [136], and to be inactive when tested a third time [143]. One of the miscellaneous compounds, albanol A (281) isolated from Broussonetia papyrifera Vent.…”

Section: Natural Product Compounds Tested For Aromatase Inhibitionmentioning

confidence: 99%

“…Moderately active flavones included broussoflavonol F (3,5,7-trihydroxy-8,3'-diprenylflavone, 10, isolated from B. papyrifera Vent.) in microsomes [135], galangin (3,5,7-trihydroxyflavone, 20) in JEG-3 cells [125], kaempferol (3,5,7,4'-tetrahydroxyflavone, 29) in JEG-3 cells [125], 5,7,4'-trihydroxy-3'-methoxyflavone (44) in microsomes [136], and rutin (5,7,3',4'-tetrahydroxyflavone 3-diglucoside, 39, isolated from Vitis L. sp.)…”

Section: Natural Product Compounds Tested For Aromatase Inhibitionmentioning

confidence: 99%

“…Structures of miscellaneous natural products (not previously mentioned) tested for aromatase inhibition. Table 1 Previous literature reports of natural product extracts tested for aromatase inhibition Brassica oleracea a [122] apigenin (8) microsomes 2.9 μM IC 50 [123] apigenin (8) microsomes 4.2 μM IC 50 [190] apigenin (8) microsomes 10 μM IC 50 [177] apigenin (8) microsomes 15 μM IC 50 [136] apigenin (8) microsomes 0.9 μg/mL IC 50 [121] apigenin (8) microsomes (modified) 2.9 μM IC 50 [124] apigenin (8) spectrophotometric w/microsomes 0.9 K s [120] apigenin (8) trout ovarian aromatase 84.0 μM IC 50 [128] apigenin (8) JEG-3 cells 0.18 μM IC 50 [125] apigenin (8) Arom+HEK 293 cells 1.4 μM IC 50 [125] apigenin (8) H295R adrenocortical carcinoma cells 20 μM IC 50 [127] apigenin (8) granulose-luteal cells inhibited at 10 μmol/L for 24 h [129] ayanin (9) microsomes 69.6 PCA at 20 μg/mL [143] broussoflavonol F (10) microsomes 7.3 PCA at 20 μg/mL [143] broussoflavonol F (10) microsomes 9.7 μM IC 50 [135] broussoflavonol F (10) SK-BR-3 cells 28.4 PCA at 50 μM [143] chrysin (11) microsomes 0.5 μM IC 50 [122] chrysin (11) microsomes 0.7 μM IC 50 [123] chrysin (11) microsomes 1.1 μM IC 50 [191] chrysin (11) microsomes 8.9 μM IC 50 [136] chrysin (11) microsomes 1.1 μg/mL IC 50 [121] chrysin (11) microsomes 1 K i [118] chrysin (11) microsomes 2.6 K i [119] chrysin (11) microsomes (modified) 0.7 μM IC 50 [124] chrysin (11) spectrophotometric w/microsomes 0.5 K s [120] chrysin (11) tro...…”

Section: Fig (2)mentioning

confidence: 99%

“…at 100 μM [107] quercetin (37) nd nd [131] robinetin (38) microsomes 45.7 μg/mL IC 50 [121] rutin (39) human preadipocyte cells none [126] rutin (39) nd~120 % inhib. at 100 μM [107] [135] eriodictyol a (50) microsomes 5.3 μM IC 50 [136] eriodictyol a (50) microsomes (modified) 0.6 μM IC 50 [133] (2S)-euchrenone a7 (51) microsomes 3.4 μM IC 50 [135] flavanone a (52) microsomes 8 μM IC 50 [122] flavanone a (52) microsomes 8 μM IC 50 [132] flavanone a (52) microsomes 28.5 μM IC 50 [137] flavanone a (52) microsomes 32 μM IC 50 [136] flavanone a (52) microsomes 250.0 μM IC 50 [128] flavanone a (52) microsomes 8.7 μg/mL IC 50 [121] flavanone a (52) microsomes (modified) 13.8 μM IC 50 [133] flavanone a (52) trout ovarian aromatase >1000 μM IC 50 [128] hesperetin a (53) microsomes 1.0 μg/mL IC 50 [121] hesperetin a (53) microsomes (modified) 3.3 μM IC 50 [133] hesperidin a (54) microsomes 40.9 μg/mL IC 50 [121] 4'-hydroxyflavanone a (55) microsomes 10 μM IC 50 [132] 7-hydroxyflavanone a (56) microsomes 3.8 μM IC 50 [138] 7-hydroxyflavanone a (56) microsomes 10 μM IC 50 [136] 7-hydroxyflavanone a (56) microsomes (modified) 2.4 μM IC 50 [133] 7-hydroxyflavanone a (56) H295R adrenocortical carcinoma cells 65 μM IC 50 [127] isoxanthohumol a (57) choriocarcinoma-derived JAR cells 139.7 μM IC 50 [114] isoxanthohumol a (57) SK-BR-3 cells 25.4 μM IC 50 [139] 7-methoxyflavanone a (58) microsomes 8.0 μM IC 50 [137] 7-methoxyflavanone a (58) microsomes (modified) 2.6 μM IC 50 [124] 7-methoxyflavanone a (58) H295R adrenocortical carcinoma cells none [127] naringenin (59 a ) microsomes 2.9 μM IC 50 [191] naringenin (59 a ...…”

Section: Fig (2)mentioning

confidence: 99%

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Natural Products as Aromatase Inhibitors

Balunas¹,

Su²,

Brueggemeier³

et al. 2008

ACAMC

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With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein. Keywordsaromatase inhibitors; natural products; breast cancer; botanical dietary supplements BREAST CANCERWorldwide breast cancer estimates included over one million incident cases and almost 400,000 deaths in the year 2000 [1,2]. In the United States, over 178,000 women were expected to be diagnosed with breast cancer in 2007 with over 40,000 deaths occurring from the disease [3]. In developed countries, mortality from breast cancer has recently begun to decline, primarily due to earlier detection and improved treatments [4,5]. Breast cancer is thought to be a result of inherited genetic predisposition (e.g., mutations in genes such as BRCA-1, p53, PTEN/MMAC1, and/or ATM) and/or environmental factors (e.g., radiation exposure, dietary factors, alcohol consumption, hormonal exposure) [2,6,7]. Numerous genetic mutations are necessary for breast cancer development and progression including the acquisition of the capabilities for self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis, known collectively as the "hallmarks of cancer" [8].Numerous molecular targets have been identified as playing a significant role in breast cancer development and progression. Estrogens and the estrogen receptors (ERs) are widely NIH Public Access Author ManuscriptAnticancer Agents Med Chem. Author manuscript; available in PMC 2011 April 12.Published in final edited form as:Anticancer Agents Med Chem. 2008 August ; 8(6): 646-682. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript recognized to play an important role in the development and progression of breast cancer, making estrogens and the ERs widely studied molecular targets [9][10][11][12]. Two of the endogenous estrogens found in humans include estradiol and estrone. In pre-menopausal women, estrogens are produced primarily through conversion of androgens in the ovaries while estrogen production in postmenopausal women occurs in only peripheral tissues [13,14]. Estrogens have various effects throughout the body, including positive effects on the brain, bone, heart, liver, and vagina, with negative effects such as increased risk...

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Resveratrol: The Biochemistry Behind Its Anticancer Effects

Kundu

Surh

2009

Plant Phenolics and Human Health

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Combining Computational and Biochemical Studies for a Rationale on the Anti‐Aromatase Activity of Natural Polyphenols

Cited by 33 publications

References 32 publications

Resveratrol: A multitargeted agent for age-associated chronic diseases

Resveratrol: A multitargeted agent for age-associated chronic diseases

Natural Products as Aromatase Inhibitors

Resveratrol: The Biochemistry Behind Its Anticancer Effects

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