Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.

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Role of Resveratrol in Prevention and Therapy of Cancer: Preclinical and Clinical Studies

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; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), 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.

Resveratrol: a multitargeted agent for age-associated chronic diseases.

Targeting cell cycle regulation in cancer therapy.

The effect of extracts from ginger rhizome on inflammatory mediator production.

Cinnamon has been used as a spice and as traditional herbal medicine for centuries. The available in vitro and animal in vivo evidence suggests that cinnamon has anti-inflammatory, antimicrobial, antioxidant, antitumor, cardiovascular, cholesterol-lowering, and immunomodulatory effects. In vitro studies have demonstrated that cinnamon may act as an insulin mimetic, to potentiate insulin activity or to stimulate cellular glucose metabolism. Furthermore, animal studies have demonstrated strong hypoglycemic properties. However, there are only very few well-controlled clinical studies, a fact that limits the conclusions that can be made about the potential health benefits of cinnamon for free-living humans. The use of cinnamon as an adjunct to the treatment of type 2 diabetes mellitus is the most promising area, but further research is needed before definitive recommendations can be made.

Cinnamon and Health

Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells.

Resveratrol analogs were newly synthesized and evaluated for cytotoxicity in cultured human lung and colon cancer cells. 3,5,4-Trimethoxy-trans-stilbene and 3,5,2',4'-tetramethoxy-trans-stilbene were found to be more potent rather than resveratrol. 3,4,5-Trimethoxy-4'-bromo-cis-stilbene was the most active among the test compounds.

Synthesis and evaluation of cytotoxicity of stilbene analogues.

5-Arylamino-2-methyl-4,7-dioxobenzothiazoles as inhibitors of cyclin-dependent kinase 4 and cytotoxic agents.

Resveratrol, a trihydroxystilbene found in grapes and several plants, has been shown to be active in inhibiting multistage carcinogenic process. Using resveratrol as the prototype, we synthesized several analogs and evaluated their growth inhibitory effect using cultured human cancer cells. In the present report we show that one of the resveratrol analogs, 3, 5,2',4'-tetramethoxy-trans-stilbene, potentiated the inhibition of cancer cell growth. Prompted by the strong growth inhibitory activity of the compound (IC50; 0.8 microg/ml) compared to resveratrol (IC50; 18.7 microg/ml) in cultured human colon cancer cells (Col2), we performed an action mechanism study using the compound. The compound induced the accumulation of cellular DNA contents in the sub-G0 phase DNA contents of the cell cycle by in a time-dependent manner. The morphological changes were also consistent with an apoptotic process. This result indicated that the compound induced apoptosis of cancer cells, and may be a candidate for use in the development of potential cancer chemotherapeutic or cancer chemopreventive agents.

Resveratrol analog, 3,5,2′,4′-tetramethoxy-trans-stilbene, potentiates the inhibition of cell growth and induces apoptosis in human cancer cells

5-Arylamino-2-methyl-4,7-dioxobenzothiazoles were synthesized as inhibitors of cyclin-dependent kinase 4 (CDK4) and cytotoxic agents. Most of the 4,7-dioxobenzothiazoles exhibited selective inhibitory activities for the CDK4 and cytotoxic potential against human cancer cell lines.

Kyung Ae Nam

Papers

Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells.

Synthesis and evaluation of cytotoxicity of stilbene analogues.

5-Arylamino-2-methyl-4,7-dioxobenzothiazoles as inhibitors of cyclin-dependent kinase 4 and cytotoxic agents.

Resveratrol analog, 3,5,2′,4′-tetramethoxy-trans-stilbene, potentiates the inhibition of cell growth and induces apoptosis in human cancer cells

5‐Arylamino‐2‐methyl‐4,7‐dioxobenzothiazoles as Inhibitors of Cyclin‐Dependent Kinase 4 and Cytotoxic Agents.