Showing papers by "John M. Pezzuto published in 2008"

Grapes and human health: a perspective.

Abstract: Grapes are a valuable source of numerous phytonutrients, including the intensively studied constituent, resveratrol. A question worth addressing is the potential of dietary grape consumption to positively modulate human health. Many studies have suggested cardiovascular benefits, and some work has indicated cancer chemopreventive activity. Data are particularly compelling in the area of skin cancer prevention. With financial support provided by the California Table Grape Commission, novel and exciting preliminary data are emerging from independent research suggesting beneficial activity against other less prevalent but devastating illnesses, such as Alzheimer's disease and urinary bladder dysfunction. It is further suggested that some of the copious amounts of data obtained with resveratrol may be relevant to grape consumption, especially responses that can be mediated by low concentrations of the substance. Whether future specific health claims will be sought from or allowed by regulatory authorities is not known, but based on existing data, it is clear that grapes should be considered an integral component of fruit and vegetable enriched diets that are recommended by health authorities and widely accepted as beneficial for human health and disease prevention.

Resveratrol as an Inhibitor of Carcinogenesis

Abstract: Given the high probability of developing cancer over the period of a normal life span, cancer chemoprevention provides an attractive therapeutic strategy for the delay or reversal of this process. ...

Natural products as inhibitors of carcinogenesis

Abstract: Background: Although carcinogenesis and cancer have been studied intensively for > 50 years, the rates of cancer incidence and mortality remain high. The most successful approach for reducing these rates has been primary prevention. For individuals at a high risk of developing cancer owing to certain genetic, environmental and occupational factors, cancer chemoprevention is a logical approach. Objective: This review discusses natural products as inhibitors of carcinogenesis. Conclusion: Natural product chemopreventive agents are inherently biologically active and have been demonstrated to prevent and reverse the carcinogenic process in a pleiotropic manner. Derivatives of compounds discovered by screening natural products for chemopreventive agents have shown efficacy in clinical trials. Despite the obstacles that must be overcome before chemopreventive drugs become an integral component of standard medical practice for cancer prophylaxis, there is vast potential for significant improvement in cancer morb...

In vitro metabolism of isoliquiritigenin by human liver microsomes.

Abstract: Isoliquiritigenin (2',4',4-trihydroxychalcone), a chalcone found in licorice root and other plants, has shown potent antitumor, antioxidant, and phytoestrogenic activity in vitro. In preparation for in vivo studies, the metabolism of isoliquiritigenin by human liver microsomes was investigated, and seven phase 1 metabolites were identified. In addition to aromatic hydroxylation that occurred on the A or B ring to form 2',4,4',5'-tetrahydroxychalcone or butein, respectively, reduction of the carbon-carbon double bond of an alpha,beta-unsaturated ketone and cyclization occurred to form 2',4,4'-trihydroxydihydrochalcone and (Z/E)-6,4'-dihydroxyaurone. All metabolites were characterized and identified by using liquid chromatography-tandem mass spectrometry with comparison to authenticated compounds. Finally, monoclonal antibody inhibitors of specific human cytochrome P450 (P450) enzymes and recombinant human P450 enzymes were used to identify the enzymes responsible for the formation of the major mono-oxygenated metabolites, and P450 2C19 was found to be a significant enzyme in the formation of butein from isoliquiritigenin, which also has anticancer activity. Cytochromes P450, reactive oxygen species, and peroxidases can all contribute to the formation of (Z/E)-6,4'-dihydroxyaurone in human liver microsomes.

Biotransformation of the Chemopreventive Agent 2′,4′,4-Trihydroxychalcone (Isoliquiritigenin) by UDP-Glucuronosyltransferases

Abstract: 2',4',4-trihydroxychalcone (isoliquiritigenin), a chalcone found in licorice root and shallots, exhibits antioxidant, estrogenic, and antitumor activities To complement our previous studies concerning the phase 1 metabolism of isoliquiritigenin, the phase 2 transformation of isoliquiritigenin by human hepatocytes and pooled human liver microsomes (HLMs) was investigated using liquid chromatography/tandem mass spectrometry and UV absorbance Five glucuronides were detected corresponding to monoglucuronides of isoliquiritigenin and liquiritigenin, but no sulfate conjugates were observed The UDP-glucuronosyltransferases (UGTs) involved in the formation of the major glucuronide conjugates were identified using recombinant human UGTs in combination with liquid chromatography/mass spectrometry UGT1A1 and UGT1A9 were the major enzymes responsible for the formation of the most abundant conjugate, isoliquiritigenin 4'-O-glucuronide (MG5), with Km values of 430+/-047 and 315+/-024 microM, respectively UGT1A1 and UGT1A10 converted isoliquiritigenin to the next most abundant phase 2 metabolite, isoliquiritigenin 2'-O-glucuronide (MG4), with Km values of 298+/-08 and 258+/-13 microM, respectively In addition, isoliquiritigenin glucuronides MG4 and MG5 were formed by pooled human intestine and kidney microsomes, respectively Based on the in vitro determination of a 253-min half-life for isoliquiritigenin when incubated with HLMs, the intrinsic clearance of isoliquiritigenin was estimated to be 364 ml/min/kg These studies indicate that isoliquiritigenin will be conjugated rapidly in the liver to form up to five monoglucuronides

Cytotoxic Activity of Some Anatolian Salvia. Extracts and Isolated Abietane Diterpenoids

Abstract: Salvia hypargeia. Fisch. et Mey. (Lamiaceae) root extract, among 16 Salvia. extracts, showed the highest activity against the human ovarian cancer cell line. Bioactivity-guided fractionation of this plant extract has yielded four abietane-type diterpenes [5,6-didehydro-7-hydroxytaxodone (1), 14-deoxycoleon U (= 6-hydroxysalvinolone) (2), demethylcryptojaponol (3), and salvicanaric acid (4)] two triterpenes (lupeol and lupeol-3-acetate), and a fatty acid mixture consisting mainly of palmitic acid (51.6%) and palmitoleic acid (6.4%). Compounds 2 and 3 were found to be active against A2780 human ovarian cancer cell line with IC50 values of 3.9 and 1.2 μ g/mL, respectively, and the fatty acid composition was the most active part of the extract (IC50 = 0.6 μ g/mL).

Mechanisms of cancer chemopreventive agents: a perspective.

Abstract: A fundamental question addressed by drug development programs is how agents being tested function on a molecular level. Using resveratrol, curcumin and EGCG as examples, it is clear that a definitive mechanism of action for cancer chemopreventive agents is not available despite decades of exhaustive research. This is profoundly evident based on the myriad of biological responses that have been observed at the cellular level, and even more overwhelming when considering gene expression data that are now available. The situation is confounded further when chemopreventive agents are used in combination, even though superior clinical responses are anticipated. The best hope for delineating tangible, meaningful mechanisms resides in the use of complex physiological systems and computer models to decipher the most critical pathways that are appropriate for targeting with chemopreventive agents, their analogues, and combination treatments. Definitive answers concerning clinical efficacy are only available through human trials. Given the enormity of these tasks, together with the urgency of continuing the fight against cancer, it is adequate to move ahead with chemopreventive drug development on a semi-empirical basis, bearing in mind the importance of limiting toxic side effects.

Dietary Administration of Asimina triloba. (Paw Paw) Extract Increases Tumor Latency in N.-Methyl-N.-nitrosourea–Treated Rats

Abstract: The paw paw tree, Asimina triloba. (L.) Dunal (Annonaceae), contains more than 50 bioactive components, primarily annonaceous acetogenins. Some therapeutic activities have been associated with this material, but the potential to mediate a cancer chemopreventive effect has not been reported. In this study, a standardized extract from the twigs, in which bullatacin, asimicin, and trilobacin represent the most potent and major bioactive acetogenins, was tested in the N.-methyl-N.-nitrosourea–induced mammary carcinogenesis model. With Sprague-Dawley rats given a diet containing paw paw extract (1250 and 2500 mg/kg diet; based on maximum tolerated dose studies), mammary tumor latency was increased from 55 to 66 days. However, mammary tumor incidence and multiplicity were not affected by extract consumption.

Zapotin prevents mouse skin tumorigenesis during the stages of initiation and promotion.

Abstract: Background: Zapotin, aflavonoid associated with Casimiroa edulis, was isolated as part of a program to discover natural inhibitors of carcinogenesis. Zapote blanco, the fruit of Casimiroa edulis, is consumed in many parts of the world. Zapotin is a non-toxic inducer of cellular differentiation, apoptosis and cell cycle arrest with cultured HL-60 promyelocytic cells. Materials and Methods: An efficient chemical synthesis for zapotin was devised. Using this synthetic material, activity was examined in the two-stage mouse skin carcinogenesis model. Results: Topical zapotin significantly inhibited 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced mouse skin tumorigenesis, using the anti-initiation and anti-promotion protocols. Conclusion: Encouraging results from previous and current in vivo studies warrant further investigation of the chemopreventive activity of zapotin.

New Approach for Evaluating the Anti-Breast Cancer Activity of Traditional Chinese Medicine

Abstract: Traditional Chinese medicine includes thousands of formulations, largely based on mixtures of terrestrial plants, and these formulations are administered for essentially all types of human diseases including cancer. Nonetheless, there are no generally accepted pre-clinical models for assessing the potential clinical efficacy of traditional Chinese medicines for treating cancer. Based on extensive analyses of traditional use for the potential treatment of human breast cancer, and systematic evaluations of the literature reports indicating mediation of well-defined bioactivities or biochemical markers consistent with control of proliferation or differentiation of cancer cells, 18 different traditional Chinese medicines have been selected as prime examples of promising leads. For the first step of the experimental approach, the herbs need to be properly identified. Next, complex formulations are produced by traditional methods under cGMP conditions and characterized by means of HPLC-fingerprints. Finally, anti-tumor or cancer preventive response can be assessed with (1) transgenic mice engineered to develop mammary adenocarcinoma, and (2) Sprague-Dawley rats bearing N-methyl-N-nitrosourea-induced mammary tumors. Animals with intact immune systems are used since this may be intimately related to the mechanism of action of traditional Chinese medicine. As a result of these procedures, a good indication of the true biologic potential of these traditional medicines should be established, and sufficient chemical and botanical information should be available to permit a smooth transition for more advanced translational studies. (17)atcm3_chap14.p65 9/11/2007, 10:09 AM 321 322 J.M. Pezzuto et al.