curcumin and dibenzoylmethane

Neuroblastoma (NB) is the most prevalent pediatric solid tumor and a leading cause of cancer-related death in children. In the present study, a novel cytotoxic role for the dietary compounds, curcumin, andrographolide, wedelolactone, dibenzoylmethane, and tanshinone IIA was identified in human S-type NB cells, SK-N-AS and SK-N-BE(2). Mechanistically, cell death appeared apoptotic by flow cytometry; however, these effects proceeded independently from both caspase-3 and p53 activation, as assessed by both genetic (shRNA) and pharmacological approaches. Notably, cell death induced by both curcumin and andrographolide was associated with decreased NFκB activity and a reduction in Bcl-2 and Bcl-xL expression. Finally, curcumin and andrographolide increased cytotoxicity following co-treatment with either cisplatin or doxorubicin, two chemotherapeutic agents widely used in the clinical management of NB. Coupled with the documented safety in humans, dietary compounds may represent a potential adjunct therapy for NB.

Topics: Abietanes; Anti-Inflammatory Agents; Antineoplastic Agents; bcl-X Protein; Caspases; Cell Death; Cell Line, Tumor; Cell Survival; Chalcones; Chromones; Coumarins; Curcumin; Diet; Diterpenes; Humans; Morpholines; Neuroblastoma; NF-kappa B; Plant Extracts; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

Curcumin, a diferuloylmethane, has been shown to exhibit anti-inflammatory and anti-proliferative activities. Whereas curcumin has both a Michael acceptor and a Michael donor units, its analogues dibenzoylmethane (DBM, a component of licorice) and dibenzoylpropane (DBP) have a Michael donor but not a Michael acceptor unit, and the analogue dibenzylideneacetone (DBA) has a Michael acceptor unit. In the current report, we investigated the potency of DBM, DBP, and DBA in relation to curcumin for their ability to suppress TNF-induced NF-κB activation, NF-κB-regulated gene products, and cell proliferation. We found that all four agents were active in suppressing NF-κB activation; curcumin was most active and DBM was least active. When examined for its ability to inhibit the direct DNA binding activity of p65, a subunit of NF-κB, only DBP inhibited the binding. For inhibition of TNF-induced IKK activation, DBA was most active. For suppression of TNF-induced expression of NF-κB-regulated gene products such as COX-2 (inflammation marker), cyclin D1 (proliferation marker), and VEGF (angiogenesis marker), DBA and curcumin were more active than DBM. Similarly for suppression of proliferation of leukemia (KBM-5), T cell leukemia (Jurkat), prostate (DU145), and breast (MDA-MB-231) cancer cells, curcumin and DBA were most active and DBP was least active. Overall, our results indicate that although curcumin and its analogues exhibit activities to suppress inflammatory pathways and cellular proliferation, a lack of Michael acceptor units in DBM and DBP can reduce their activities.

Topics: Angiogenic Proteins; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Cell Proliferation; Chalcones; Curcumin; Gene Expression Regulation; Humans; MAP Kinase Kinase Kinases; Molecular Structure; Pentanones; Tumor Necrosis Factor-alpha

Aberrant arachidonic acid metabolism is involved in the inflammatory and carcinogenic processes. In this study, we investigated the effects of curcumin, a naturally occurring chemopreventive agent, and related beta-diketone derivatives on the release of arachidonic acid and its metabolites in the murine macrophage RAW264.7 cells and in HT-29 human colon cancer cells. We also examined their effects on the catalytic activities and protein levels of related enzymes: cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenases (COX) as well as 5-lipoxygenase (5-LOX). At 10 micro M, dibenzoylmethane (DBM), trimethoxydibenzoylmethane (TDM), tetrahydrocurcumin (THC) and curcumin effectively inhibited the release of arachidonic acid and its metabolites in lipopolysaccharide (LPS)-stimulated RAW cells and A23187-stimulated HT-29 cells. Inhibition of phosphorylation of cPLA(2), the activation process of this enzyme, rather than direct inhibition of cPLA(2) activity appears to be involved in the effect of curcumin. All the curcuminoids (10 micro M) potently inhibited the formation of prostaglandin E(2) (PGE(2)) in LPS-stimulated RAW cells. Curcumin (20 micro M) significantly inhibited LPS-induced COX-2 expression; this effect, rather than the catalytic inhibition of COX, may contribute to the decreased PGE(2) formation. Without LPS-stimulation, however, curcumin increased the COX-2 level in the macrophage cells. Studies with isolated ovine COX-1 and COX-2 enzymes showed that the curcuminoids had significantly higher inhibitory effects on the peroxidase activity of COX-1 than that of COX-2. Curcumin and THC potently inhibited the activity of human recombinant 5-LOX, showing estimated IC(50) values of 0.7 and 3 micro M, respectively. The results suggest that curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cPLA(2), decreasing the expression of COX-2 and inhibiting the catalytic activities of 5-LOX. These activities may contribute to the anti-inflammatory and anticarcinogenic actions of curcumin and its analogs.

Topics: Animals; Antineoplastic Agents; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Benzoates; Cells, Cultured; Chalcones; Colonic Neoplasms; Curcumin; Cytosol; Dinoprostone; Enzyme Inhibitors; Humans; Lipopolysaccharides; Macrophages; Phospholipases A; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Sheep

Dietary factors play important roles in the carcinogenic process. The results of epidemiological data and some laboratory animal studies indicate that certain naturally occurring and synthetic components are able to block the carcinogenic process and inhibit the development of certain cancers. Dibenzoylmethane (DBM), a curcumin-related beta-diketone analogue has been reported to exhibit a remarkable inhibitory effect on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in Sencar mice. The present study investigated the possible mechanisms of inhibitory action of DBM on DMBA-induced mammary tumorigenesis in mice. The summarized results indicate that: (1) in in-vitro studies. DBM inhibited DMBA metabolism and the formation of DMBA-DNA adducts in a dose-dependent manner; (2) in the assay of competitive binding to estrogen receptors with [3H]-estradiol in vitro, DBM showed weak binding affinity; (3) in vivo, feeding of 1% DBM in the diet of immature Sencar mice for 4 -5 weeks decreased the uterine and parametrial fat pad weights, and lowered the serum estrogen and triglyceride levels. This study provides insight into the mechanisms involved in the inhibitory action of DBM in mouse mammary tumorigenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Benzoates; Binding, Competitive; Carcinogens; Cattle; Chalcones; Curcumin; Cytosol; Dietary Fats; DNA; DNA Adducts; DNA Damage; Drug Screening Assays, Antitumor; Estradiol; Female; Hypolipidemic Agents; Mammary Neoplasms, Experimental; Mice; Mice, Inbred SENCAR; Microsomes, Liver; Molecular Structure; Ovariectomy; Progesterone; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Spices; Triglycerides; Uterus

Curcumin is a beta-diketone constituent of the spice turmeric that possesses anticarcinogenic properties in several animal models. The present studies were conducted in order to identify beta-diketones structurally-related to curcumin that would be effective dietary blocking agents toward the initiation stage of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis. Of the beta-diketone compounds initially screened for their capacity to induce quinone-reductase (QR) activity in wild-type Hepa1c1c7 cells and a mutant subclone, curcumin (diferuloylmethane) and dibenzoylmethane were most effective. However, when added to semipurified diets fed to female rats, dibenzoylmethane (1%), but not curcumin (1%), was effective in inhibiting in vivo mammary DMBA-DNA adduct formation. This inhibitory effect on mammary adduct formation was associated with a significant increase in liver activities of glutathione S-transferase, QR and 7-ethoxyresorufin-O-deethylase activities. Female rats provided diets supplemented with dibenzoylmethane at 0.1, 0.5 and 1.0% for 14 days prior to dosing with DMBA exhibited a significant decrease in mammary tumor development, compared with controls. However, tumor development for animals fed diets containing 1.0% curcumin was not different from that of controls. Therefore, dibenzoylmethane, and possibly other structurally-related beta-diketones, warrant examination as breast cancer chemopreventative blocking agents.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Benzoates; Carcinogens; Chalcones; Curcumin; DNA Adducts; Female; Liver Neoplasms, Experimental; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Rats; Rats, Sprague-Dawley

Female Sencar mice (6 weeks old) were administered 1 mg of 7,12-dimethylbenz[a]anthracene (DMBA) by oral gavage once a week for 5 weeks. At 20 weeks after the first dose of DMBA, 68% of mice developed mammary tumors (the average 1.08 tumors per mouse) and 45% had lymphomas/leukemias. Feeding 1% dibenzoylmethane (DBM) in AIN 76A diet, starting at 2 weeks before the first dose of DMBA and continuing until the end of the experiment, inhibited both the multiplicity and incidence of DMBA-induced mammary tumor by 97%. The incidence of lymphomas/leukemias was completely inhibited by 1% DBM diet. In contrast, feeding 2% curcumin diet had little or no effect on the incidence of mammary tumors, and the incidence of lymphomas/leukemias was reduced by 53%.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Benzoates; Chalcones; Curcumin; Female; Leukemia, Experimental; Lymphoma; Mammary Neoplasms, Experimental; Mice