Curcumin Bio

Curcumin's utility is limited by its aqueous insolubility. We have demonstrated a heat-mediated 12-fold increase in curcumin's aqueous solubility. Here, we show by SDS-PAGE and surface plasmon resonance that heat-solubilised curcumin binds to proteins. Based on this binding we hypothesized that heat-solubilized curcumin or turmeric would prevent autoantibody targeting of cognate autoantigens. Heat-solubilized curcumin/turmeric significantly decreased binding of autoantibodies from Sjögren's syndrome (up to 43/70%, respectively) and systemic lupus erythematosus (up to 52/70%, respectively) patients as well as an animal model of Sjögren's syndrome (up to 50/60%, respectively) to their cognate antigens. However, inhibition was not specific to autoimmunity. Heat-solubilised curcumin/turmeric also inhibited binding of commercial polyclonal anti-spectrin to spectrin (50/56%, respectively). Thus, we suggest that the multifaceted heat-solubilized curcumin can ameliorate autoimmune disorders. In addition, the non-toxic curcumin could serve as a new protein stain in SDS-PAGE even though it is less sensitive than the Coomassie system, which involves toxic chemicals.

Curcumin Combinations

Several studies have indicated that curcumin's anti-cancer actions appear to also be enhanced with it is combined with green tea extract (EGCG). Combination of curcumin and green tea catechins prevents dimethylhydrazine-induced colon carcinogenesis.

Combination of curcumin and green tea catechins prevents dimethylhydrazine-induced colon carcinogenesis.

Xu G, Ren G, Xu X, Yuan H, Wang Z, Kang L, Yu W, Tian K. Food Chem Toxicol. 2009 Oct 24.

The chemopreventive effects of curcumin and green tea catechins individually and in combination on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis were studied in male Wister rats following 32 weeks of dietary treatment. The incidence, number and size of colorectal cancer were measured. Colorectal aberrant crypt foci (ACF) were analysed by methylene blue staining. Proliferation indices and apoptotic indices were determined by PCNA immunostaining and TUNEL assay respectively. The results showed that dietary curcumin, catechins and combination administration significantly inhibited the total number of ACF per rat. The combination treatment displayed the most potent inhibitory effect, while there was no difference of inhibition between curcumin and catechins-treated groups. The incidence of colorectal cancer in the treated groups was significantly lower than that of positive control group. Compared with the positive control group, the proliferation index was significantly decreased and the apoptotic index was significantly increased in all treatment groups, while the effect of the combination was the greatest among the treated groups. Our findings suggest that the combination of curcumin and catechins produces a synergistic colon cancer-preventative effect that would be more potent than each of the compounds alone.

Curcumin inhibits prosurvival pathways in chronic lymphocytic leukaemia B cells and may overcome their stromal protection in combination with EGCG

Ghosh AK, Kay NE, Secreto CR, Shanafelt TD. Clin Cancer Res. 2009 Feb 15;15(4):1250-8.

Chronic lymphocytic leukaemia (CLL): The effects of curcumin on the viability of primary CLL B cells and its ability to overcome stromal mediated protection was studies. The in vitro effect of curcumin on primary CLL B cells was evaluated using fluorescence activated cell sorter analysis and Western blotting. For some experiments, CLL B cells were cocultured with human stromal cells to evaluate the effects of curcumin on leukaemia cells cultured in their microenvironment. Finally, the effect of curcumin in combination with the green tea extract epigallocatechin-3 gallate (EGCG) was evaluated. RESULTS: Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 micromol/L) manner and inhibited constitutively active prosurvival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor kappaB.

Moreover, curcumin suppressed expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and up-regulated the pro-apoptotic protein BIM. Coculture of CLL B cells with stromal cells resulted in elevated levels of STAT3, increased expression of Mcl-1 and XIAP, and decreased sensitivity to curcumin. When curcumin was administered simultaneously with EGCG, antagonism was observed for most patient samples. In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death and could overcome stromal protection. CONCLUSIONS: Curcumin treatment was able to overcome stromal protection of CLL B cells on in vitro testing and to synergize with EGCG when administered in a sequential fashion.

Modulatory Effects of Curcumin and Green Tea Extract against Experimentally Induced Pulmonary Fibrosis: A Comparison with N-Acetyl Cysteine

Hamdy MA, El-Maraghy SA, Kortam MA., J Biochem Mol Toxicol. 2012 Nov 6. doi: 10.1002/jbt.21447.

The study was aimed to investigate the protective effect of green tea extract (GTE), curcumin, and N acetyl cysteine (NAC) on experimentally induced pulmonary fibrosis. Curcumin (200 mg/kg b.w), GTE (150 mg/kg b.w), and NAC (490 mg/kg b.w) were administered orally for 14 days with concomitant administration of cyclophosphamide (CP). Lung fibrosis was assessed by measuring hydroxyproline and elastin levels and confirmed by histopathological examination. Oxidative stress was also observed in the CP group. Lung myeloperoxidase activity was significantly decreased in animals of the CP group. N-acetyl-beta-d-glucosaminidase, leukotriene C(4) , and protein were increased in bronchoalveolar lavage fluid (BALF). All modulators markedly attenuated the altered biochemical parameters as compared to CP-treated rats. These results suggest the possibility of using these treatments as protective agents with chemotherapy and as protective agents for lung fibrosis.

The combination of EGCG and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo.

Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP, Rosengren RJ. Int J Cancer. 2008 May 1;122(9):1966-71.

Both Epigallocatchin gallate (EGCG) and curcumin have shown efficacy in various in vivo and in vitro models of cancer. This study was designed to determine the efficacy of these naturally derived polyphenolic compounds in vitro and in vivo, when given in combination. Studies in MDA-MB-231 cells demonstrated that EGCG + curcumin was synergistically cytotoxic and that this correlated with G(2)/M-phase cell cycle arrest. After 12 hr, EGCG (25 microM) + curcumin (3 microM) increased the proportion of cells in G(2)/M-phase to 263 +/- 16% of control and this correlated with a 50 +/- 4% decrease in cell number compared to control. To determine if this in vitro result would translate in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with curcumin (200 mg/kg/day, po), EGCG (25 mg/kg/day, ip), EGCG + curcumin, or vehicle control (5 ml/kg/day, po) for 10 weeks. Tumour volume in the EGCG + curcumin treated mice decreased 49% compared to vehicle control mice (p < 0.05), which correlated with a 78 +/- 6% decrease in levels of VEGFR-1 protein expression in the tumours. Curcumin treatment significantly decreased tumour protein levels of EGFR and Akt, however the expression of these proteins was not further decreased following combination treatment. Therefore, these results demonstrate that the combination of EGCG and curcumin is efficacious in both in vitro and in vivo models of ER alpha-breast cancer and that regulation of VEGFR-1 may play a key role in this effect.

Synergistic anticancer activity of curcumin and catechin: an in vitro study using human cancer cell lines.

Manikandan R, Beulaja M, Arulvasu C, Sellamuthu S, Dinesh D, Prabhu D, Babu G, Vaseeharan B, Prabhu NM. Microsc Res Tech. 2012 Feb;75(2):112-6. doi: 10.1002/jemt.21032. Epub 2011 Jul 21.

The most practical approach to reduce morbidity and mortality of cancer is to delay the process of carcinogenesis by usage of anticancer agents. This necessitates that safer compounds are to be critically examined for anticancer activity especially, those derived from natural sources. A spice commonly found in India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa and the major active component is a phytochemical termed curcumin. Green tea is one of the most popular beverages used worldwide, produced from the leaves of evergreen plant Camellia sinensis and the major active ingredients are polyphenolic compounds known as catechins. In this study, synergistic anticancer activity of curcumin and catechin was evaluated in human colon adenocarcinoma HCT 15, HCT 116, and human larynx carcinoma Hep G-2 cell lines. Although both curcumin or catechin inhibited the growth of above cell lines, interestingly, in combination of both these compounds highest level of growth control was observed. The anticancer activity shown is due to cytotoxicity, nuclear fragmentation as well as condensation, and DNA fragmentation associated with the appearance of apoptosis. These results suggest that curcumin and catechin in combination can inhibit the proliferation of HCT 15, HCT 116, as well as Hep G-2 cells efficiently through induction of apoptosis.

Epigallocatechin-3-gallate potentiates curcumin's ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis.

Kondo A, Takeda T, Li B, Tsuiji K, Kitamura M, Wong TF, Yaegashi N. Int J Clin Oncol. 2012 Feb 15.

Uterine leiomyosarcoma (LMS) has an unfavourable response to standard chemotherapeutic regimens. Two natural occurring compounds, curcumin and epigallocatechin gallate (EGCG), are reported to have anti-cancer activity. We previously reported that curcumin reduced uterine LMS cell proliferation by targeting the AKT-mTOR pathway. However, challenges remain in overcoming curcumin's low bioavailability.

The human LMS cell line SKN was used. The effect of EGCG, curcumin or their combination on cell growth was detected by MTS assay. Their effect on AKT, mTOR, and S6 was detected by Western blotting. The induction of apoptosis was determined by Western blotting using cleaved-PARP specific antibody, caspase-3 activity and TUNEL assay. Intracellular curcumin level was determined by a spectrophotometric method. Antibody against EGCG cell surface receptor, 67-kDa-laminin receptor (67LR), was used to investigate the role of the receptor in curcumin's increased potency by EGCG.

In this study, we showed that the combination of EGCG and curcumin significantly reduced SKN cell proliferation more than either drug alone. The combination inhibited AKT, mTOR, and S6 phosphorylation, and induced apoptosis at a much lower curcumin concentration than previously reported. EGCG enhanced the incorporation of curcumin. 67LR antibody partially rescued cell proliferation suppression by the combination treatment, but was not involved in the EGCG-enhanced intracellular incorporation of curcumin. EGCG significantly lowered the concentration of curcumin required to inhibit the AKT-mTOR pathway, reduce cell proliferation and induce apoptosis in uterine LMS cells by enhancing intracellular incorporation of curcumin, but the process was independent of 67LR.

Synergism from sequenced combinations of curcumin and epigallocatechin-3-gallate with cisplatin in the killing of human ovarian cancer cells.

Yunos NM, Beale P, Yu JQ, Huq F. Anticancer Res. 2011 Apr;31(4):1131-40.

Drug resistance remains an on-going challenge in ovarian cancer chemotherapy. The objective of this study was to determine the effect on synergism in activity from the sequenced combinations of cisplatin (Cis) with curcumin (Cur) and epigallocatechin-3-gallate (EGCG) in the human ovarian cancer cell lines. The drugs were added in binary combinations: Cis combined with Cur, and Cis combined with EGCG to the human ovarian A2780 and A2780(cisR) cancer cell lines, using five different sequences of administration: 0/0 h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The combination index (CI) was used to assess the combined action of the drugs. CIs <1, =1 and >1 indicated synergism, addictiveness and antagonism respectively. Cellular accumulation of platinum and platinum-DNA binding levels from Cis and its combination with the phytochemicals were determined using graphite furnace atomic absorption spectrometry. Addition of Cis 4 h before Cur and EGCG (0/4 h combination) produced the most synergistic outcomes in both the A2780 and A2780(cisR) cell lines. The cellular accumulations of platinum and platinum-DNA binding resulting from the 0/4 h combinations were greater as compared to the values using Cis alone, thus providing an explanation for the synergistic action. When sequenced combinations of Cis with Cur and with EGCG are applied to human ovarian A2780 and A2780(cisR) cancer cell lines, lower concentrations and shorter time gap between the two additions seem to produce a higher cytotoxic effect.

Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9.

Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu H, Geng M, Shen K.

Molecules. 2013 Jan 8;18(1):701-20. doi: 10.3390/molecules18010701.

Curcumin, a principal component of turmeric (Curcuma longa), has potential therapeutic activities against breast cancer through multiple signalling pathways. Increasing evidence indicates that curcumin reverses chemo-resistance and sensitizes cancer cells to chemotherapy and targeted therapy in breast cancer. To date, few studies have explored its potential antiproliferation effects and resistance reversal in antiestrogen-resistant breast cancer. In this study, we therefore investigated the efficacy of curcumin alone and in combination with tamoxifen in the established antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9. We discovered that curcumin treatment displayed anti-proliferative and pro-apoptotic activities and induced cell cycle arrest at G2/M phase. Of note, the combination of curcumin and tamoxifen resulted in a synergistic survival inhibition in MCF-7/LCC2 and MCF-7/LCC9 cells. Moreover, we found that curcumin targeted multiple signals involved in growth maintenance and resistance acquisition in endocrine resistant cells. In our cell models, curcumin could suppress expression of pro-growth and anti-apoptosis molecules, induce inactivation of NF-kB, Src and Akt/mTOR pathways and downregulates the key epigenetic modifier EZH2. The above findings suggested that curcumin alone and combinations of curcumin with endocrine therapy may be of therapeutic benefit for endocrine-resistant breast cancer.

Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy.

Chatterjee SJ, Pandey S. Cancer Biol Ther. 2011 Jan 15;11(2):216-28. Epub 2011 Jan 15.

Melanoma is the deadliest form of skin cancer, which is notoriously aggressive and chemo-resistant, and for which there is little effective treatment available if it goes undetected. Curcumin from the turmeric spice (Curcuma longa) has long been used in Southeast Asian medicine to alleviate ailments and cure an array of diseases and disorders. It possesses anti-inflammatory, anti-oxidant and most importantly anti-carcinogenic activity. There have been contradictory reports discussing the efficacy of curcumin-induced death on melanoma. In this report we show that curcumin does induce apoptosis in A375 and the relatively resistant G361 malignant human melanoma cell lines at higher doses. Tamoxifen is an oestrogen receptor (ER) blocker that is used for ER positive breast cancer treatment. Recently, tamoxifen has been shown to directly target the mitochondria. Given that curcumin is a pro oxidant and tamoxifen can act on mitochondria, we ask whether the combinatorial treatment could result in synergistic induction of apoptosis in chemo-resistant melanoma. Our results show a corresponding increase in phosphatidyl serine flipping, mitochondria depolarization and reactive oxygen species (ROS) generation by the combined treatment at lower doses. Interestingly, there was significant induction of autophagy along with apoptosis following the combined treatment. Importantly, non-cancerous cells are unaffected by the combination of these non-toxic compounds. However, once exposed to low doses of this co-treatment, melanoma cells still retain signals to commit suicide even after removal of the drugs. This combination provides a non-toxic option for combinatorial chemotherapy with great potential for future use.

Effect of the o-methyl catechols apocynin, curcumin and vanillin on the cytotoxicity activity of tamoxifen.

Pedroso LS, Fvero GM, de Camargo LE, Mainardes RM, Khalil NM. J Enzyme Inhib Med Chem. 2013 Aug;28(4):734-40. doi: 10.3109/14756366.2012.680064.

Apocynin (APO), curcumin (CUR) and vanillin (VAN) are o-methyl catechols widely studied due their antioxidant and antitumour properties. The effect of treatment with these o-methyl catechols on tamoxifen (TAM)-induced cytotoxicity in normal and tumour cells was studied. The cytotoxicity of TAM on red blood cells (RBC) was performed by haemoglobin or K(+)release and on polymorphonuclear leukocytes (PMNs) by trypan blue dye exclusion method. Cytotoxic activity was assessed in human chronic myeloid leukaemia (K562) cell line by (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). According the release of haemoglobin and K(+), the CUR showed a decrease in TAM cytotoxicity on RBC; however, in PMN, APO, CUR and VAN showed increased of these cells viability. VAN presented the highest cytotoxicity on K562 cells, followed by APO and CUR. These results point the potential therapeutic value of these o-methyl catechols with TAM, particularly of CUR, which potentiates the cytotoxic effects of TAM on K562 cells and also decreases TAM-associated cytotoxicity on RBC and PMN.

Amelioration of tamoxifen-induced liver injury in rats by grape seed extract, black seed extract and curcumin.

El-Beshbishy HA, Mohamadin AM, Nagy AA, Abdel-Naim AB. Indian J Exp Biol. 2010 Mar;48(3):280-8.

Liver injury was induced in female rats using tamoxifen (TAM). Grape seeds (Vitis vinifera) extract (GSE), black seed (Nigella sativa) extract (NSE), curcumin (CUR) or silymarin (SYL) were orally administered to TAM-intoxicated rats. Liver histopathology of TAM-intoxicated: rats showed pathological changes. TAM-intoxication elicited declines in liver antioxidant enzymes levels (glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase), reduced glutathione (GSH) and GSH/GSSG ratio plus the hepatic elevations in lipid peroxides, oxidized glutathione (GSSG), tumour necrosis factor-alpha (TNF-alpha) and serum liver enzymes; alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase levels. Oral intake of NSE, GSE, CUR or SYL to TAM-intoxicated rats, attenuated histopathological changes and corrected all parameters mentioned above. Improvements were prominent in case of NSE (similarly SYL) > CUR > GSE. Data indicated that NSE, GSE or CUR act as free radical’s scavengers and protect TAM-induced liver injury in rats.

Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells.

Chuang SE, Yeh PY, Lu YS, Lai GM, Liao CM, Gao M, Cheng AL. Biochem Pharmacol. 2002 May 1;63(9):1709-16.

Nuclear factor-kappaB (NF-kappaB) has been implicated in the development of drug resistance in cancer cells. We systematically examined the baseline levels of NF-kappaB activity of representative carcinoma cell lines, and the change of NF-kappaB activity in response to a challenge with four major anticancer drugs (doxorubicin, 5-fluorouracil, cisplatin, and paclitaxel). We found that the basal level of NF-kappaB activity was heterogeneous and roughly correlated with drug resistance. When challenged with various drugs, all the cell lines examined responded with a transient activation of NF-kappaB, which then declined to basal level despite variation in the concentration of the agent, and the timing of the treatment. In contrast to tumour necrosis factor-alpha (TNF-alpha), which activates NF-kappaB in minutes, NF-kappaB activation induced by anticancer drugs usually occurred more than 1hr after stimulation. A gradual increase of total NF-kappaB and its nuclear translocation, and cytoplasmic translocation of nuclear IkappaBalpha and its degradation were involved in this process. In particular, when cells were pre-treated with common biologic modulators such as tamoxifen, dexamethasone, and curcumin, the doxorubicin-induced NF-kappaB activation was attenuated significantly. This inhibition may play a role in sensitizing cancer cells to chemotherapeutic drugs. This study has demonstrated that activation of NF-kappaB is a general cellular response to anticancer drugs, and the mechanism of activation appears to be distinct from that induced by TNF-alpha. These observations may have implications for improving the efficacy of systemic chemotherapy for cancer patients.

Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro studies: a possible therapy to alleviate autoimmune disorders.

Kurien, B.T., D'Souza, A. & Scofield, R.H. Molecular Nutrition & Food Research. Volume 54 Issue 8, Pages 1202-09. DOI:10.1002/mnfr.200900106

Curcumin's utility is limited by its aqueous insolubility. We have demonstrated a heat-mediated 12-fold increase in curcumin's aqueous solubility. Here, we show by SDS-PAGE and surface plasmon resonance that heat-solubilised curcumin binds to proteins. Based on this binding we hypothesized that heat-solubilized curcumin or turmeric would prevent autoantibody targeting of cognate autoantigens. Heat-solubilized curcumin/turmeric significantly decreased binding of autoantibodies from Sjögren's syndrome (up to 43/70%, respectively) and systemic lupus erythematosus (up to 52/70%, respectively) patients as well as an animal model of Sjögren's syndrome (up to 50/60%, respectively) to their cognate antigens. However, inhibition was not specific to autoimmunity. Heat-solubilised curcumin/turmeric also inhibited binding of commercial polyclonal anti-spectrin to spectrin (50/56%, respectively). Thus, we suggest that the multifaceted heat-solubilized curcumin can ameliorate autoimmune disorders. In addition, the non-toxic curcumin could serve as a new protein stain in SDS-PAGE even though it is less sensitive than the Coomassie system, which involves toxic chemicals.

Several studies have indicated that curcumin’s anti-cancer actions appear to also be enhanced with it is combined with green tea extract (EGCG).

Combination of curcumin and green tea catechins prevents dimethylhydrazine-induced colon carcinogenesis.

Xu G, Ren G, Xu X, Yuan H, Wang Z, Kang L, Yu W, Tian K. Food Chem Toxicol. 2009 Oct 24.

The chemopreventive effects of curcumin and green tea catechins individually and in combination on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis were studied in male Wister rats following 32 weeks of dietary treatment. The incidence, number and size of colorectal cancer were measured. Colorectal aberrant crypt foci (ACF) were analysed by methylene blue staining. Proliferation indices and apoptotic indices were determined by PCNA immunostaining and TUNEL assay respectively. The results showed that dietary curcumin, catechins and combination administration significantly inhibited the total number of ACF per rat. The combination treatment displayed the most potent inhibitory effect, while there was no difference of inhibition between curcumin and catechins-treated groups. The incidence of colorectal cancer in the treated groups was significantly lower than that of positive control group. Compared with the positive control group, the proliferation index was significantly decreased and the apoptotic index was significantly increased in all treatment groups, while the effect of the combination was the greatest among the treated groups. Our findings suggest that the combination of curcumin and catechins produces a synergistic colon cancer-preventative effect that would be more potent than each of the compounds alone.

Quercetin

Quercetin is widely distributed in the plant kingdom and is the most abundant of the flavonoid molecules. It is found in many often-consumed foods, including apple, onion, tea, berries, and brassica vegetables, as well as many seeds, nuts, flowers, barks, and leaves. It is also found in medicinal botanicals, including Ginkgo biloba, Hypericum perforatum (St. John's Wort), Sambucus canadensis (Elder), and many others. It is often a major component of the medicinal activity of the plant, and has been shown in experimental studies to have numerous effects on the body.

All flavonoids have the same basic chemical structure, a three-ringed molecule with hydroxyl (OH) groups attached. A multitude of other substitutions can occur, giving rise to the many types of flavonoids. Flavonoids often occur in foods as a glycoside, meaning they have a sugar molecule (rhamnose, glucose, galactose, etc.) attached to the centre (C) ring. Quercetin is the aglycone (meaning minus the sugar molecule) of a number of other flavonoids, including rutin, quercetin, isoquercetin, and hyperoside. These molecules have the same structure as quercetin except they have a specific sugar molecule in place of one of quercetin's hydroxyl groups on the C ring, which dramatically changes the activity of the molecule. Activity comparison studies have identified other flavonoids as often having similar effects as quercetin; but quercetin usually has the greatest activity.

Quercetin appears to have many beneficial effects on human health, including cardiovascular protection, anti-cancer activity, anti-ulcer effects, anti-allergy activity, cataract prevention, antiviral activity, and anti-inflammatory effects."

Actions

Flavonoids, as a rule, are antioxidants, and a number of quercetin's effects appear to be due to its antioxidant activity. Quercetin scavenges oxygen radicals, inhibits xanthine oxidase, and inhibits lipid peroxidation in vitro. As another indicator of its antioxidant effects, quercetin inhibits oxidation of LDL cholesterol in vitro, probably by inhibiting LDL oxidation itself, by protecting vitamin E in LDL from being oxidized or by regenerating oxidized vitamin E. By itself, and paired with ascorbic acid, quercetin reduced the incidence of oxidative damage to neurovasculature structures in skin, and inhibited damage to neurons caused by experimental glutathione depletion.

Quercetin's anti-inflammatory activity appears to be due to its antioxidant and inhibitory effects on inflammation-producing enzymes (cyclooxygenase, lipoxygenase) and the subsequent inhibition of inflammatory mediators, including leukotrienes and prostaglandins. Inhibition of histamine release by mast cells and basophils also contributes to quercetin's anti-inflammatory activity.

Aldose reductase, the enzyme that catalyses the conversion of glucose to sorbitol, is especially important in the eye, and plays a part in the formation of diabetic cataracts. Quercetin is a strong inhibitor of human lens aldose reductase.

Quercetin exerts antiviral activity against reverse transcriptase of HIV and other retroviruses, and was shown to reduce the infectivity and cellular replication of Herpes simplex virus type 1, poliovirus type 1, parainfluenza virus type 3, and respiratory syncytial virus (RSV).

Early studies on quercetin reported that administration to rats caused an increased incidence of urinary bladder tumours. Subsequent studies on rats, mice, and hamsters were unable to confirm the potential carcinogenicity of this molecule. In fact, much of the recent research on quercetin has shown it to be an anticarcinogenic to numerous cancer cell types, including breast, leukaemia, colon, ovary, squamous cell, endometrial, gastric, and non-small-cell lung.

Indications

Quercetin: Works like an antihistamine, treats allergies, prevents heart disease and Cancer.

Speed up healing of recurrent heartburn, or gastroesophogeal reflux disorder (GERD)

Epstein-Barr virus may be suppressed.

Diabetic neuropathies.

Allergies: Quercetin's mast-cell-stabilizing effects make it an obvious choice for use in preventing histamine release in allergy cases, similar to the synthetic flavonoid analogue cromolyn sodium. Absorption of the pure aglycone quercetin is poor (see below); however, much of quercetin's anti-allergy effects may be due to anti-inflammatory and anti-histaminic effects in the gut.

Cardiovascular Disease Prevention: Quercetin's cardiovascular effects centre on its antioxidant and anti-inflammatory activity, and its ability to inhibit platelet aggregation ex vivo. The Zutphen Elderly Study investigated dietary flavonoid intake and risk of coronary heart disease. The risk of heart disease mortality decreased significantly as flavonoid intake increased. Individuals in the upper 25 per cent of flavonoid intake had a relative risk of 0.42 compared to the lowest 25 per cent in this 5-year follow-up study of men ages 65-84. Interestingly, the flavonoid-containing foods most commonly eaten in this study contain a high amount of quercetin (tea, onions, apples). In a cohort of the same study, dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence.

Anti-ulcer/Gastro protective effects: Animal studies have shown quercetin to be protective of gastric ulceration caused by ethanol, probably by inhibiting lipid peroxidation of gastric cells and/or by inhibition of gastric acid secretion. An interesting aspect of quercetin's anti-ulcer effect is that it has been shown to inhibit growth of Helicobacter pylori in a dose-dependent manner in vitro.

Cancer: As mentioned above, quercetin has been investigated in a number of animal models and human cancer cell lines, and has been found to have antiproliferative effects. It may also increase the effectiveness of chemotherapeutic agents. More clinically oriented research needs to be done in this area to discover effective dosage ranges and protocols.

Diabetic Complications: Quercetin's aldose reductase-inhibiting properties make it a useful addition to diabetic nutritional supplementation, to prevent cataract and neurovascular complications.

Viral Infections: Quercetin may be useful in viral infections; however, none of the research so far is clinically based. Even so, concentration on ingesting quercetin-rich foods or supplementation with the pure substance may be helpful during viral illnesses."

Pharmacokinetics

Few human quercetin absorption studies exist. A recent study of absorption in "healthy" ileostomy patients revealed an absorption of 24 per cent of the pure aglycone and 52 per cent of quercetin glycosides from onions. However, no intestinal permeability values were obtained in this group, and thus the results might not be reliable. Quercetin undergoes bacterial metabolism in the intestinal tract, and is converted into phenolic acids. Absorbed quercetin is transported to the liver bound to albumin, where some may be converted via methylation, hydroxylation, or conjugation.

Similarly Quercetin has been shown to have significant anti-oxidant and ant-inflammatory properties in human studies (Boots et al,. 2008), which directly infers protection against certain cancers, however direct studies involving human clinical trials and Quercetin are inadequate. Quercetin is a safe ingredient that has suggestive research of its prophylactic properties with no contradicting studies to suggest no benefit or harm. One study in fact revealed that combining Curcumin and Quercetin together has beneficial results, potentially working in synergy.

One such trial looked at Curcumin & Quercetin treatment in a resistant genetic disease caused Familial Adenomatous Polyposis where hundreds of colorectal polyps form and later transform into colorectal cancer. Supplementation with high dose curcumin and quercetin revealed a significant reduction in both the number and size of polyps in each patient. Although the number of patients in this study was small, accurate assessment size and number of patients’ pre-cancerous polyps were recorded with colonoscopy from gastroenterologists. “Results: Patients had a decreased polyp number and size from baseline after a mean of 6 months of treatment with curcumin and quercetin. The mean per cent decrease in the number and size of polyps from baseline was 60.4% (P < .05) and 50.9% (P < .05), respectively.” The Johns Hopkins University School of Medicine, and Marcia Cruz-Correa, M.D., Ph.D., at Johns Hopkins and the University of Puerto Rico School of Medicine were very impressed with the results and stated: “This study showed for the first time that curcumin treatment was efficacious in decreasing the number of polyps in patients with FAP, similarly to what has been seen with the use of synthetic NSAID agents, but with minimal side effects. Furthermore, we saw that adenomas found in the small intestine of our patients also responded to curcumin (Cruz-Correa et al., 2006). Larger Randomized trials are now being developed to further assess Curcumin and Quercetin’s role in colorectal diseases.

We therefore believe that Curcumin and Quercetin have a valuable role in the multidisciplinary therapeutic plan of patients with certain colorectal diseases and as chemoprophylaxis or adjunctive cancer therapy as well as CVD.

Research supporting the therapeutic and prophylactic effects of Curcumin & Quercetin

By Dr Daniel Weber, PhD MSc & Dr James Laporta MBChB(UCT), DMH(SA)

Curcumin is most well known as one of the active compounds in traditional Turmeric curry spice, and has been extensively researched in-vitro with proven anti-oxidant, ant-inflammatory, and anti-amyloid activity (Lim et al,. 2001; Reddy & Lokesh, 1992; Sreejayan& Rao, 1994; Shih & Lin, 1993; Kim et al, 2001) As such, research has extended to several randomised control trials and other open label studies.

Quercetin, a member of the flavonoids family, has been shown in vitro to provide protection against various diseases such as osteoporosis, certain forms of cancer, pulmonary and cardiovascular diseases but also against ageing. Especially the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical is suggested to be involved in these possible beneficial health effects (Boots et al., 2000; Kamaraj et al., 2007).

Dietary bioactive food components that interact with the immune response have a considerable potential to reduce the risk of cancer. Numerous substances identified in fruits and vegetables have the ability to modulate the effects of deregulated cell cycle checkpoints and contribute to prevention of cancer.

Not only curcumin, but also numerous other plant-origin agents, possess this potential, among them apigenin (celery, parsley), epigallocatechin-3-gallate (green tea), resveratrol (red grape, peanuts, and berries), genistein (soybean), and silymarin - Milk thistle (Bengmark, 2006).

Curcumin and many other plant-derived substances are increasingly regarded as shields against disease (Bengmark, 2006). Curcumin is the most explored of a family of the so-called active chemopreventive substances in the spice turmeric, collectively referred to as curminoids.

Various preparations of Curcuma longa have been used traditionally in Ayurvedic medicine, Indian medicine, and Chinese medicine, with long-term anecdotal use and historical safety. Active chemical compounds include diferuloylmethane, demethoxycurcumin, bisdemethoxycurcumin, cyclocurcumin, and several others that may contribute to its medicinal properties.

This document serves to illustrate the therapeutic and prophylactic value of Curcumin by focusing on the anti-cancer potential of Curcumin with particular importance given to colon cancer; and including randomised control trials on Curcumin & Quercetin’s effect on ulcerative colitis.

References

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