Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.

28th Tuesday, 2010  |   Others, Uncategorized  |  no comments

Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to oestrogen; therefore, these plant chemicals are thought

to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5, 7-dihydroxyflavone), 7,8-dihydroxyflavone, baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4,5,7-trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and six human aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones.
Kao YC, Zhou C, Sherman M, Laughton CA, & Chen S. Environ Health Perspect. 1998 February; 106(2): 85–92.

Prevention and Therapy of Cancer by Dietary Monoterpenes

26th Sunday, 2010  |   Herb or Compound  |  no comments

Monoterpenes are nonnutritive dietary components found in the essential oils of citrus fruits and other plants. A number of these dietary monoterpenes have antitumor activity. For example, d-limonene, which comprises .90% of orange peel oil, has chemopreventive activity against rodent mammary, skin, liver, lung and forestomach cancers. Similarly, other dietary monoterpenes have chemopreventive activity against rat mammary, lung and forestomach cancers when fed during the initiation phase. In addition, perillyl alcohol has promotion phase chemopreventive activity against rat liver cancer, and geraniol has in vivo antitumor activity against murine leukemia cells. Perillyl alcohol and d-limonene also have chemotherapeutic activity against rodent mammary and pancreatic tumors. As a result, their cancer chemotherapeutic activities are under evaluation in Phase I clinical trials. Several mechanisms of action may account for the antitumor activities of monoterpenes. The blocking chemopreventive effects of limonene and other monoterpenes during the initiation phase of mammary carcinogenesis are likely due to the induction of Phase II carcinogen-metabolizing enzymes, resulting in carcinogen detoxification. The post-initiation phase, tumor suppressive chemopreventive activity of monoterpenes may be due to the induction of apoptosis and/or to inhibition of the post-translational isoprenylation of cell growth-regulating proteins. Chemotherapy of chemically induced mammary tumors with monoterpenes results in tumor redifferentiation concomitant with increased expression of the mannose-6-phosphate/insulin-like growth factor II receptor and transforming growth factor b1. Thus, monoterpenes would appear to act through multiple mechanisms in the chemoprevention and chemotherapy

of cancer. Crowell PL. Prevention and Therapy of Cancer by Dietary Monoterpenes. J. Nutr. 129: 775S–778S, 1999.

Cancer Prevention by Natural Compounds. Drug Metabolism and Pharmacokinetics.

26th Sunday, 2010  |   Herb or Compound  |  no comments

Increasing attention is being paid to the possibility of applying cancer chemopreventive agents for individuals at high risk of neoplastic development. For this purpose by natural compounds have practical advantages with regard to availability, suitability for oral application, regulatory approval and mechanisms of action. Candidate substances such as phytochemicals present in foods and their derivatives have been identified by a combination of epidemiological and experimental studies. Plant constituents include vitamin derivatives, phenolic and flavonoid agents, organic sulfur compounds, isothiocyanates, curcumins, fatty acids and d-limonene. Examples of compounds from animals are unsaturated fatty acids and lactoferrin. Recent studies have indicated that mechanisms underlying chemopreventive potential may be combinations of anti-oxidant, anti-inflammatory, immune-enhancing, and anti-hormone effects, with modification of drug-metabolizing enzymes, influence on the cell cycle and cell differentiation, induction of apoptosis and suppression of proliferation and angiogenesis playing roles in the initiation and secondary modification stages of neoplastic development. Accordingly, natural agents are advantageous for application to humans because of their combined mild mechanism. Here we review naturally occurring compounds useful for cancer chemprevention based on in vivo studies with reference to their structures, sources and mechanisms of action.
Tsuda H, Ohshima Y, Nomoto H, et al. Cancer Prevention by Natural Compounds. Drug Metabolism and Pharmacokinetics. Drug Metabolism and Pharmacokinetics. Vol. 19 (2004) , No. 4 pp.245-263

d -Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis

26th Sunday, 2010  |   Herb or Compound  |  no comments

Limonene takes its name from the lemon, as the rind of the lemon, like other citrus fruits, contains considerable amounts of this compound, which contributes to their odor. Limonene is a chiral molecule, and biological sources produce one enantiomer: the principal industrial source, citrus fruit, contains D-limonene ((+)-limonene), which is the (R)-enantiomer (CAS number 5989-27-5, EINECS number 227-813-5).

Racemic limonene is known as dipentene.[1] D-Limonene is obtained commercially by extraction from orange peel with liquid CO2.
Clinical trials have shown that docetaxel combined with other novel agents can improve the survival of androgen-independent prostate cancer patients. d -Limonene, a non-nutrient dietary component, has been found to inhibit various cancer cell growths without toxicity. We sought to characterize whether a non-toxic dose of d -limonene may enhance tumor response to docetaxel in an in vitro model of metastatic prostate cancer. Results show, for the first time, that d -limonene enhanced the antitumor effect of docetaxel against prostate cancer cells without being toxic to normal prostate epithelial cells. The combined beneficial effect could be through the modulation of proteins involved in mitochondrial pathway of apoptosis. d -Limonene could be used as a potent non-toxic agent to improve the treatment outcome of hormone-refractory prostate cancer with docetaxel.
Rabi T, Bishayee A. d -Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis. Journal of carcinogenesis 2009;8:9.

Herbs That Influence COX-2 Expression

26th Sunday, 2010  |   Herb or Compound  |  no comments

Chuan Xiong-Ligusticum Chuanxiong
Essential Oil of Ligusticum Chuanxiong Hort’s Influence on Expressions of COX-2 in Hypothalamus of Fever Rat
Objective: to investigate the antipyretic mechanism of Essential oil of Ligusticum chuanxiong Holt (CH). Methods: The expressions of COX -2 protein in hypothalamus of brewer’s yeast-induced fever rats were checked using Immunohistochemistry. Results: The expressions of COX -2 protein in hypotbalamus of model team are higher than normal team, expressions of teams of high and middle dose of CH are lower than model team, expression of team of low dose of CH has no obvious different with model team. Conclusion: one of the anfipyretie mechanism of essential oil of Ligustieum ehuanxiong Hort. (CH) may be to inhibit the expression of COX-2 protein in hypothalamus of rats, thereby reduce the content of PGE2 that lower the set point and produce anfipyrefie effect (Yang et al 2008).

Cui Yun Cao-Selaginella uncinata
Inhibiting Action of Total Flavones from Selaginella uncinata on COX-2 mRNA Expression in HT-29 Cells
Objective: To investigate the action of total flavones from Selaginella uncinata ( Desv. ) Spring on cyclooxygenase-2 (COX-2) mRNA expression in carcinoma of colon cell line HT-29 ,and explore related molecular mechanism thereby. Method: Total flavones from Selaginella uncinata was used on TH-29 cells and there were four groups including high-dose group, midst-dose group, low-dose group and negative control group. The morphological change of the cells was observed by inverted microscope. The expressions of COX-2 mRNA were measured using reverse transcription polymerase chain reaction (RT-PCR) method. Caraphoresis gel photo auto- analysis system was used to detect the products. Result: Comparing with the negative control group, the total flavonoids groups could significantly inhibit the expressions of the COX-2 mRNA level in a dose-dependent manner. Conclusion: It can be concluded that the mechanisms may be that the total flavonoids can inhibit COX-2 in mRNA level. Then it can inhibit COX-2 protein expression. It may be one of the anti-tumor mechanisms of Selaginella uncinata (Sun, Chen & Liu, 2010).

Deng Long Guo-Physalis peruviana
Supercritical carbon dioxide extract exhibits enhanced antioxidant and anti-inflammatory activities of Physalis peruviana.
Physalis peruviana L. (PP) is a medicinal herb widely used in folk medicine. In this study, supercritical carbon dioxide (SFE-CO2) method was employed to obtain three different PP extracts, namely SCEPP-0, SCEPP-4 and SCEPP-5. The total flavonoid and phenol concentrations, as well as antioxidant and anti-inflammatory activities of these extracts were analyzed and compared with aqueous and ethanolic PP extracts. Among all the extracts tested, SCEPP-5 demonstrated the highest total flavonoid (234.63+/-9.61 mg/g) and phenol (90.80+/-2.21 mg/g) contents. At concentrations 0.1-30 microg/ml, SCEPP-5 also demonstrated the strongest superoxide anion scavenging activity and xanthine oxidase inhibitory effect. At 30 microg/ml, SCEPP-5 significantly prevented lipopolysaccharide (LPS; 1 microg/ml)-induced cell cytotoxicity in murine macrophage (Raw 264.7) cells. At 10-50 microg/ml, it also significantly inhibited LPS-induced NO release and PGE2 formation in a dose-dependent pattern. SCEPP-5 at 30 microg/ml remarkably blocked the LPS induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Taken together, these results suggest that SCEPP-5, an extract of SFE-CO2, displayed the strongest antioxidant and anti-inflammatory activities as compared to other extracts. Its protection against LPS-induced inflammation could be through the inhibition of iNOS and COX-2 expression (Wu et al 2006).

Meyskens CA et al. Chemoprevention of nonmelanoma skin cancer with celecoxib: A randomized, double-blind, placebo-controlled trial. J Natl Cancer Inst 2010 Nov 29; [e-pub ahead of print]. (

Meyskens FL Jr and McLaren CE. Chemoprevention, risk reduction, therapeutic prevention, or preventive therapy? J Natl Cancer Inst 2010 Nov 29; [e-pub ahead of print]. (

Sun Yingzhen; Chen Keli & Liu Zhen. Zhong Guo Yao Shi. 2010; (2): 163-164.

Wu SJ, Tsai JY, Chang SP, Lin DL, Wang SS, Huang SN, Ng LT. J Ethnopharmacol. 2006 Dec 6;108(3):407-13. Epub 2006 Jun 2

Yang Jin-rong, SONG Jun, HU Rong, Li Zulun, Zhang Quansen. Cheng Du Zhong Yi Yao Da Xue Xue Bao. 2008; 31(3): 38-39.