Different Curcuminoids Inhibit T-Lymphocyte Proliferation Independently of Their Radical Scavenging Activities

Deters, Michael; Knochenwefel, Heiko; Lindhorst, Daniel; Koal, Therese; Meyer, H.; Hänsel, Wolfram; Resch, Klaus; Kaever, Volkhard

doi:10.1007/s11095-008-9579-2

Cited by 46 publications

(28 citation statements)

References 23 publications

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“…The reduced metabolites, tetra-, hexa-, and octahydrocurcumin, have either greatly decreased or different biological activity compared with curcumin (43)(44)(45). In a few instances the biological activities of the putative degradation products vanillin, ferulic acid, and feruloylmethane were investigated, and these were also found to be only weakly active, at best, when compared with the same effects of curcumin (10,12,46,47). There is the possibility, however, that the quinone methide intermediate or the bicyclopentadione product are biologically active and responsible for some of the activities of curcumin.…”

Section: Discussionmentioning

confidence: 99%

Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent Curcumin

Grießer

Pistis

Suzuki

et al. 2011

Journal of Biological Chemistry

132

196

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The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chemical and metabolic instability. Non-enzymatic degradation has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degradation. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 M/min) and associated with stoichiometric uptake of O 2 . Oxidation was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nM; 7.5 M/min), and the rate was increased ≈10-fold by the addition of 300 M H 2 O 2 . The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymatic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H 2 18 O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidation to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.The yellow plant phenolic pigment curcumin shows a remarkable ability to affect a wide variety of signaling pathways that are dysregulated during tumorigenesis, including proliferation, invasion, apoptosis, and cell cycle checkpoints (1).Altogether more than one hundred molecular targets of curcumin have been identified using in vitro cell culture-based assays (2). The diversity of biological effects of curcumin has been attributed to its ability to act as an antioxidant, anti-inflammatory, and anti-viral agent (3). As a consequence of promising in vitro results, several clinical trials have been initiated to investigate the effect of dietary curcumin in the prevention of inflammatory bowel disease, colon, and pancreatic cancer, and Alzheimer Disease, among others (3).Prior to the more recent interest in its chemopreventive properties, curcumin was being considered as a food coloring agent but its chemical and photochemical instability prevented widespread application. Light-induced degradation of curcumin in organic solvents results in cleavage of the heptadienone chain, and the most abundant products have been identified as vanillin, ferulic aldehyde, ferulic acid, and feruloylmethane (4, 5). The same products have been observed as degradation products of curcumin in aqueous buf...

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Section: Discussionmentioning

confidence: 99%

Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent Curcumin

Grießer

Pistis

Suzuki

et al. 2011

Journal of Biological Chemistry

132

196

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“…Previous studies have indicated that the active sites of curcumin and tetrahydrocurcumin related to their antioxidative activity are composed of hydroxy and carbonyl groups located in the centers of their chemical structures (15). Furthermore, it has been reported that curcuminoids inhibit T-lymphocyte proliferation independently of their radical scavenging activity; the inhibitory effects were dependent on the number of carbon atoms and doubles of the 1,6-heptadiene-3,5-dione structure as well as on the phenolic ring substitutes of the curcuminoids, and were not correlated to their respective radical scavenging activity (25). Curcumin, tetrahydrocurcumin and monoacetylcurcumin all include hydroxy plus carbonyl groups (Fig.…”

Section: Discussionmentioning

confidence: 99%

Monoacetylcurcumin strongly regulates inflammatory responses through inhibition of NF-κB activation

Nishida

Nishiumi²,

Mizushina³

et al. 2010

Int J Mol Med

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Abstract. Curcumin, a component of turmeric (Curcuma longa), is known to exert a variety of biological functions including anti-inflammatory activity. We examined the inhibitory effects of chemically synthesized derivatives of curcumin against inflammatory responses and compared them with those of curcumin, in order to find derivatives with stronger effects than curcumin. In a cell culture system using the mouse macrophage cell line RAW264.7, monoacetylcurcumin strongly inhibited IκB phosphorylation, nuclear factor (NF)-κB activation and tumor necrosis factor (TNF)-· production induced by lipopolysaccharide (LPS). In addition, oral administration of monoacetylcurcumin to mice led to greater suppression of TNF-· production after LPS stimulation than the administration of curcumin or tetrahydrocurcumin in vivo. Monoacetylcurcumin also inhibited the LPS-induced NF-κB activation in the liver. Collectively, monoacetylcurcumin is a potential chemopreventive agent for treating inflammatory responses more effectively than curcumin.

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“…Cell numbers and viability were then estimated on the basis of trypan blue exclusion by counting in Vi-Cell™ XR cell viability analyzer (Beckman Coulter Inc., Fullerton, CA). PBMC proliferation was determined by the standard 3 H-thymidine incorporation assay (22,23). Briefly, cells were treated in 96-well plates (10 5 cells/well) with either ethanol and/or DMSO vehicle (control) or CUR, CA and SIL, alone and in combination, in the presence of 35 μg/ml phytohemagglutinin (PHA), for 54 h. Negative control cells were incubated with vehicle in the absence of PHA.…”

Section: Methodsmentioning

confidence: 99%

Distinct Combinatorial Effects of the Plant Polyphenols Curcumin, Carnosic Acid, and Silibinin on Proliferation and Apoptosis in Acute Myeloid Leukemia Cells

Pesakhov

Khanin

Studzinski

et al. 2010

Nutrition and Cancer

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Acute myeloid leukemia (AML) is a malignancy without effective treatment for most patients.Here we demonstrate that combinations of the dietary plant polyphenols curcumin and carnosic acid, at non-cytotoxic concentrations of each agent, produced a synergistic antiproliferative effect and a massive apoptotic cell death in HL-60 and KG-1a human AML cells. In contrast, combinations of curcumin and another plant polyphenol silibinin had a predominantly additive cytostatic effect, without pronounced cytotoxicity. Neither polyphenol combination affected viability of normal human fibroblasts or proliferating and non-proliferating blood cells. Early stage of curcumin/carnosic acid-induced apoptosis was associated with cleavage (activation) of caspases-8, -9, and -3 and the proapoptotic protein Bid, but not with oxidative stress or altered levels of other Bcl-2 family proteins (Bcl-2, Bcl-xL, Mcl-1, Bax and Bak). Inhibitors of caspase-8 and -9 markedly attenuated apoptosis, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Caspase-8 inhibition abrogated Bid cleavage and strongly reduced caspase-9 activation, suggesting that the cross-talk mechanism mediated by caspase-8-dependent Bid cleavage can contribute to the activation of the intrinsic apoptotic pathway by CUR+CA. Collectively, these results suggest a mechanistic basis for the potential use of dietary plant polyphenol combinations in the treatment and prevention of AML.

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Different Curcuminoids Inhibit T-Lymphocyte Proliferation Independently of Their Radical Scavenging Activities

Cited by 46 publications

References 23 publications

Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent Curcumin

Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent Curcumin

Monoacetylcurcumin strongly regulates inflammatory responses through inhibition of NF-κB activation

Distinct Combinatorial Effects of the Plant Polyphenols Curcumin, Carnosic Acid, and Silibinin on Proliferation and Apoptosis in Acute Myeloid Leukemia Cells

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