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Resveratrol: Twenty Years of Growth, Development and Controversy
John M. Pezzuto 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.1
Resveratrol was first isolated in 1939 by Takaoka from Veratrum grandiflorum O. Loes. Following this discovery, sporadic descriptive reports appeared in the literature. However, spurred by our seminal paper published nearly 60 years later, resveratrol became a household word and the subject of extensive investigation. Now, in addition to appearing in over 20,000 research papers, resveratrol has inspired monographs, conferences, symposia, patents, chemical derivatives, etc. In addition, dietary supplements are marketed under various tradenames. Once resveratrol was brought to the limelight, early research tended to focus on pharmacological activities related to the cardiovascular system, inflammation, and cancer but, over the years, the horizon greatly expanded. Around 130 human clinical trials have been (or are being) conducted with varying results. This may be due to factors such as disparate doses (ca. 5 to 5,000 mg/day) and variable experimental settings. Further, molecular targets are numerous and a dominant mechanism is elusive or nonexistent. In this context, the compound is overtly promiscuous. Nonetheless, since the safety profile is pristine, and use as a dietary supplement is prevalent, these features are not viewed as detrimental. Given the ongoing history of resveratrol, it is reasonable to advocate for additional development and further clinical investigation. Topical preparations seem especially promising, as do conditions that can respond to anti-inflammatory action and/or direct exposure, such as colon cancer prevention. Although the ultimate fate of resveratrol remains an open question, thus far, the compound has inspired innovative scientific concepts and enhanced public awareness of preventative health care.
Natural Modulators of Estrogen Biosynthesis and Function as Chemopreventive Agents
Bhat, Krishna P.L.,Pezzuto, John M. The Pharmaceutical Society of Korea 2001 Archives of Pharmacal Research Vol.24 No.6
There is clearly a need for novel breast cancer chemopreventive agents with enhanced potency and specificity with tittle or no side effects. To this end, several new chemical moieties have been synthesized or isolated from natural sources. In this reviewal we have described some agents currently in use or under development for treatment or prevention of breast cancer, as well as our own strategies for the discovery of natural product modulators of estrogen biosynthesis and function. In particulars bioassay-guided fractionation of active plant extracts is a unique method for identifying agents with novel mechanisms of action, some of which should be useful for prevention of human cancer. Further, with the advent of combinatorial chemistry and high throughput screening, even greater progress may now be expected with natural product leads.
Lee, Sang-Kook,Pezzuto, John-M. The Pharmaceutical Society of Korea 1999 Archives of Pharmacal Research Vol.22 No.6
In order to discover new cancer chemopreventive agents from natural or synthetic products, a structurally diverse class of chemopreventive agents was evaluated using in vitro biomarker of inhibition of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in cultured mouse epidermal 308 (ME)308 cells. As a results, apigenin, benzylisothiocyanate, curcumin, diallyl disulfide, N-(4-hydroxyphenyl)retinamide (4-HPR), menadione, miconazole, nordihydroguaiaretic acid (NDGA) and phenethyl isothiocyanate showed potent inhibitory effects in this process. A chemically diverse group of compounds was included in the evaluation, such as flavonoids, retinoids, isothiocyanates, sulfur-containing compounds and phenolic antioxidant compounds. These data are suggestive to understand the cancer chemopreventive potential mediated by these substances.
Suaib Luqman,Abha Meena,Laura E. Marler,Tamara P. Kondratyuk,John M. Pezzuto 한국식품영양과학회 2011 Journal of medicinal food Vol.14 No.11
Target-specific drugs, including natural products, offer promise for the amelioration of cancer and other human ailments. Capsaicin, the pungent ingredient present in chilies (Capsicum annuum L.), and capsazepine, a synthetic analog of capsaicin (collectively referred to as vanilloids), are known to possess a variety of pharmacological and physiological properties. In our continuous effort to discover and characterize cancer chemopreventive agents from natural products, we investigated the effect of vanilloids on nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) activation using stably transfected 293/NFκB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor-α (TNFα) and on aromatase activity. Capsaicin and capsazepine blocked TNFα-induced NFκB activation in a dose-dependent manner with 50% inhibitory concentration (IC_50) values of 0.68 and 4.2 μM, respectively. No significant cytotoxicity was observed at the highest concentrations tested (53.1 μM for capsazepine and 65.5 μM for capsaicin). In addition, these vanilloids inhibited aromatase activity with IC50 values of 13.6 and 8.8 μM, respectively. Computer-aided molecular docking studies showed docking scores indicative of good binding affinity of vanilloids with aromatase and NFκB. The highly conserved residues for capsaicin and capsazepine binding with NFκB p50 were Ser299 and Ile278 (H-bond 2.81Å) and with NFκB p100 were Ser6, Arg82, Val86, Arg90 (H-bond 2.89Å), Gly4, and Ser2 (H-bond 2.81Å). The amino acids Trp224, Arg435, and Val373 (H-bond 2.80Å) were found to be important for the binding of capsaicin and capsazepine with aromatase. Based on these findings, aromatase and NFκB are suggested as valid targets for these compounds; additional investigation of chemopreventive or chemotherapeutic potential is required.
LEE, SANG KOOK,HEO, YOEN HOI,STEELE, VERNON E.,PEZZUTO, JOHN M. 梨花女子大學校 藥學硏究所 2002 藥學硏究論文集 Vol.- No.11
Using a cultured human colon cancer cell line (Col2), a structurally diverse group of chemopreventive agents wasevaluated for their potential to induce apoptosis. As a rerslt, 1,4-phenylenebis(methylene)selenocyanate (p-xylylselenocyanate; P-XSC) was found to be active in this process. p-XSC, a syntheticorganoselenium compound, has been shown to inhibit tobacco-specific 4- (methylnitrosoamino)-(3-pyridyl)-l-butanone-inducedtumorigenesis in A/J mouse Iung,rat tongue carcinogenesis andcolon cancer. Known chemopreventive mechanisms includeinhibition of DNA methylation, inhibition of thymidine kinaseand reduction of oxidative DNA damage, In order to assessapoptosis induction, the cells were exposed to variousconcentrations of test substances for 48 hours. Enrichment ofmono-and oligonucleosomes in the cytoplasm was monitored asan indication of apoptosis using an ELISA kit As a result.p-XSC caused dose-dependent enrichment of fragmentednucleosomes. In Further studies, p-XSC was found to induceDNA laddering in a dose-dependent manner, while apoptoticcells accumulated in a time-dependent manner up to 96 hours.THe apoptptic peaks after tretmrnt of p-XSC were also found asconfirmed by the flow cytometric analysis of cell cycledistribution. In an additional study, however, p-XSC-mediatedapoptosis was not shown to be dependent on p53 expression.Taken together, these results suggest that induction of apoptosisis one possible mechanism for the cancer chernopreventiveactivity mediated by p-XSC.
Inhibition of Aromatase Activity by Flavonoids
Jeong, Hyeh-Jean,Shin, Young-Geun,Kim, Il-Hyuk,Pezzuto, John-M. The Pharmaceutical Society of Korea 1999 Archives of Pharmacal Research Vol.22 No.3
In searching for potent cancer chemopreventive agents from synthetic or natural products, 28 randomly selected flavonoids were screened for inhibitory effects against partially purified aromatase prepared form human placenta. Over 50% of the flavonoids significantly inhibited aromatase activity, with greatest activity being demonstrated with apigenin $(IC_{50}: 0.9{\mu}/mL)$, chrysin $(IC_{50}: 1.1{\mu}/mL)$ , and hesperetin $(IC_{50}:1.0{\mu}/mL)$.
5-(4-Hydroxyphenethenyl)-4,7-dime-thoxycoumarin, a New Constituent of Monotes engleri
Seo, Eun-Kyoung,Chai, Hee-Byung,Chagwedera, Tangai E.,Farnsworth, Norman R.,Cordell, Geoffrey A.,Pezzuto, John M.,Kinghorn, A. Douglas 梨花女子大學校 藥學硏究所 2000 藥學硏究論文集 Vol.- No.9
A new coumarin, 5-(4-hydroxyphenethenyl)-4,7-dimethoxycoumarin (1) was isolated from the combined ethyl acetate extracts of the root bark, root wood and stem bark of Monotes engleri, and found to be cytotoxic against two cell lines in a human tumor panel. Its structure was determined on the basis of spectroscopic methods.
Youn, Ui Joung,Park, Eun-Jung,Kondratyuk, Tamara P.,Sang-Ngern, Mayuramas,Wall, Marisa M.,Wei, Yanzhang,Pezzuto, John M.,Chang, Leng Chee American Chemical Society and American Society of 2016 Journal of natural products Vol.79 No.6
<P>A new fatty acid ester disaccharide, 2-O-(beta-D-glucopyranosyl)-1-O-(2E,4Z,7Z)-deca-2,4,7-trienoyl-beta-D-glucopyranose (1), a new ascorbic acid derivative, 2-caffeoyl-3-ketohexulofuranosonic acid gamma-lactone (2), and a new iridoid glycoside, 10-dimethoxyfermiloside (3), were isolated along with 13 known compounds (4-16) from fermented noni fruit juice (Morinda citrifolia). The structures of the new compounds, together with 4 and 5, were determined by 1D and 2D NMR experiments, as well as comparison with published values. Compounds 2 and 7 showed moderate inhibitory activities in a TNF-alpha-induced NF-kappa B assay, and compounds 4 and 6 exhibited considerable quinone reductase-1 (QR1) inducing effects.</P>