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Cooking enhances curcumin anti-cancerogenic activity through pyrolytic formation of "deketene curcumin"
Abstract
Curcumin is widely used in traditional Asian kitchen as a cooking ingredient. Despite its low bioavailability, epidemiological data, on low cancer incidence in Asia, suggest beneficial health effects of this compound. Therefore, the question arose whether cooking modifies the anti-cancerogenic effects of curcumin. To evaluate this, we pyrolysed curcumin with and without coconut fat or olive oil, and analysed the products by high-performance liquid chromatography (HPLC). A number of more hydrophilic curcumin isoforms and decomposition products, including a compound later identified by nuclear magnetic resonance spectroscopy (NMR) as "deketene curcumin" (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one), formerly described as a synthetic curcumin derivative, were detected. Additionally, we proved that deketene curcumin, compared to curcumin, exhibits higher toxicity on B78H1 melanoma cells resulting in G2 arrest. In conclusion, deketene curcumin is formed as a consequence of pyrolysis during common household cooking, showing stronger anti-cancer effects than curcumin. Moreover, we propose a chemical reaction-pathway for this process.
... With herbal plants used as medicine, roasting conditions have been reported to significantly affect the phytochemical contents [5], which therefore might alter their therapeutic effects [6]. In the case of turmeric, research has been focused on studying the effects of heat processing, including roasting, on the changes in phytochemical constituents [7], curcuminoid contents [8], antioxidant activities [9] and pharmacological functions such as anti-cancerogenic or anti-inflammatory effects [10,11]. However, it is likely that the influences induced by thermal processing on each therapeutic function of turmeric are different. ...
... However, it is likely that the influences induced by thermal processing on each therapeutic function of turmeric are different. For example, Sun et al. [9] observed that heat treatment decreased the neuroprotective functions of turmeric, while, in contrast, other studies reported that these processes enhanced the anti-cancerogenic and anti-inflammatory effects of curcumin [10,11]. The results therefore indicated that the influences of thermal processing nned to be verified in accordance with each target medicinal use. ...
... Turmeric has various traditional processing methods described in classical books of Materia medica, in which the conditions established for each thermal process are also different among countries, such as in China [13], India [10] and Vietnam [1,2]. It is likely that each processing method is established to meet the medicinal requirements for a specific clinical syndrome [13]. ...
Processing with heat treatment has been reported to alter several therapeutic effects of turmeric. In Vietnamese traditional medicine, turmeric has been long used for bacterial infections, and roasting techniques are sometimes applied with this material. However, there have been no studies investigating the effects of these thermal processes on the plant’s antibacterial properties. Our study was therefore performed to examine the changes that roasting produced on this material. Slices of dried turmeric were further subjected to light-roasting (80 °C in 20 min) or dark-roasting (160 °C in 20 min) processes. Broth dilution and agar-well diffusion methods were applied to examine and compare the effects of ethanol extracts obtained from non-roasted, light-roasted and dark-roasted samples, on a set of 6 gram-positive and gram-negative bacteria. In both investigations, dark-roasted turmeric was significantly less antibacterial than non-roasted and light-roasted materials, as evident by the higher values of minimum inhibitory concentrations and the smaller diameters of induced inhibitory zones. In addition, dark-roasting was also found to clearly reduce curcumin contents, total polyphenol values and antioxidant activities of the extracts. These results suggest that non-roasting or light-roasting might be more suitable for the processing of turmeric materials that are aimed to be applied for bacterial infections.
... Only 30% of the initial curcumin remained after being roasted for 5 min, whereas there was no significant accumulation of ferulic acid although a relatively lower concentration 4vinyl guaiacol got formed as the major product after further degradation. According to reports, this degradation finally leads to the formation volatile phenolic compounds like vanillin, guaiacol and isoeugenol [52]. ...
... Curcumin is very susceptible to variations in pH and heat, with the dicarbonyl bridge in its structure being the most vulnerable [52,53]. However, in case of the volatile degradation products, the first carbon of the alkyl chain that connects two catechol moieties is the most vulnerable to heat [53,54]. ...
... formation of volatiles during degradation, which is typically a decarboxylation reaction that gets accelerated by exposure to air and heat [51]. From investigations, heat treatment at 180 °C for 50 min of curcumin led to highest formation of 4-vinyl guaiacol whereas exposure to longer roasting period showed a decrease in its concentration of 4-vinyl guaiacol which further got degraded to diketene curcumin [52]. Thus, for the optimization of biological activity of plant bioactives including curcumin, fine tuning processing parameters prove to be critical [55]. ...
The current scenario of global trends impacts the way in which food is consumed and packed, meaning that change is inevitable and just around the horizon in terms of making food packaging eco-friendlier and more sustainable. Scientific advancements over the past decades have led to a wide spectrum of solutions to this problem in terms of smart, active, and antimicrobial packaging systems. The increasing demand for sustainability paves the way as a golden opportunity for these systems as they have the ability to incorporate biobased precursors like curcumin through advancements in the field of the invisible enabler, biochemistry. Investigating the properties of curcumin as a bioagent can change the dynamics of the current food packaging industry, owing to its non-toxic and eco-friendly nature and a plethora of pharmacological properties. Curcumin is the principal curcuminoid of the golden spice turmeric. Being derived from a ferulic acid, it shows excellent antimicrobial properties against bacterial pathogens like Staphylococcus aureus, Listeria monocytogenes, and Escherichia coli, and fungal cultures such as Penicillium spp. and Candida albicans. This makes it a potential agent in the food packaging industry and used as a natural food additive, dietary supplement, and pH indicator. Curcumin encapsulation has been explored with polymer matrices like polyvinyl alcohol [PVOH], low-density polyethylene [LDPE], polyvinyl acetate [PVAC], polylactic acid [PLA], etc. It has also been studied with metals like zinc as a complex which demonstrated an increase in the bioavailability of curcumin. This article aims to further explore the potential applications of curcumin in eco-friendly and antimicrobial packaging systems, and understand its importance as a bioagent.
Graphical Abstract
... According to literature data, curcumin is highly susceptible in terms of thermal induced degradation or varying pH conditions 15,[20][21][22] . The dicarbonyl bridge in the curcumin molecule is its most vulnerable structural feature. ...
... This reaction is a typical decarboxylation reaction that is accelerated by free exposure to air and higher temperatures 16 . Under the conditions investigated, a heat treatment of 50 minutes resulted in the highest formation 4-vinyl guaiacol, whereas longer roasting times were accompanied by a decrease in the concentration of 4-vinyl guaiacol which in turn is further degraded or reconstituted to the so called ''deketene curcumin'' (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) 15 . ...
... For instance, it has been shown that the degree of roasting correlates with the efficiency of counteracting inflammation and inducing Nrf2 activity in coffee 28 . Furthermore, it has been recently shown that cooking modulates the anticarcinogenic activity of curcumin due to pyrolytic formation of the already mentioned ''deketene curcumin'' (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4pentadiene-3-one) as suggested by Dahmke et al. 15 . Herein is reported that roasted curcumin and its major degradation product 4-vinyl guaiacol exhibit, by in large, a similar Nrf2 inducing activity like curcumin per se. ...
Curcumin is a secondary plant metabolite present in Curcuma longa L. Since curcumin is widely used as a food colorant in thermally processed food it may undergo substantial chemical changes which in turn could affect its biological activity. In the current study, curcumin was roasted at 180 °C up to 70 minutes and its kinetic of degradation was analyzed by means of HPLC-PDA and LC-MS, respectively. Roasting of curcumin resulted in the formation of the degradation products vanillin, ferulic acid, and 4-vinyl guaiacol. In cultured hepatocytes roasted curcumin as well as 4-vinyl guaiacol enhanced the transactivation of the redox-regulated transcription factor Nrf2, known to be centrally involved in cellular stress response and antioxidant defense mechanisms. The antioxidant enzyme paraoxonase 1 was induced by roasted curcumin and 4-vinyl guaiacol. Furthermore, roasted curcumin and 4-vinyl guaiacol decreased interleukin-6 gene expression in lipopolysaccharide stimulated murine macrophages. Current data suggest that curcumin undergoes degradation due to roasting and its degradation product exhibit significant biological activity in cultured cells.
... On the other hand, in samples treated for 5 min using a microwave, for which the determined antioxidant activity was the lowest, the concentration of curcumin was high, but the content of two other curcuminoids was the lowest, which might prove that all three curcuminoids are significant for the high antioxidant activity of the turmeric rhizome. Studies by Dahmke et al. [35] also proved that curcumin previously subjected to the cooking process (frying on a pan at 250 • C) showed higher bioactivity-both antioxidant and anti-cancer properties. A reverse relationship was observed in the case of microwave processing. ...
... As turmeric is often heated prior to consumption, the knowledge on the behavior of its single components is needed. Our studies showed a similar tendency to the results published by other researchers, who showed that the longer the time of the thermal treatment (cooking), the content of polyphenolic compounds in a sample and its antioxidant activity increased [35,37]. ...
Curcuma longa L. (Zingiberaceae), known as turmeric, is a perennial tuberous plant from the genus Curcuma, which includes about 100 plant species. The chemical composition of the turmeric rhizome is very diverse. Diarylheptanoid derivatives, also known as curcuminoids (of which curcumin, demethoxycurcumin and bisdemethoxycurcumin are the most important representatives), are the major active constituents of the plant rhizome. Many extracts used in the food and pharmaceutical industries are produced from thermally processed rhizome, when there are significant changes in the composition of the main compounds. Therefore, the aim of the study was to compare how the type of thermal treatment affects the content of curcuminoids and the antioxidant properties of the rhizome. The plant material was subjected to three different methods of thermal processing—microwave heating, boiling and frying in different time intervals. The chemical composition and antioxidant activity of the processed rhizome was evaluated using LC-MS (liquid chromatography–mass spectrometry), HPLC (high-performance liquid chromatography) and spectrophotometric methods (a DPPH test and TPC assay). Obtained results revealed that curcumin was the major curcuminoid present in all samples (113.92 mg/g of the fresh rhizome). Significant correlation between the type and time of the thermal processing and the composition of turmeric samples was revealed. A traditional boiling process lasting for 10 min was the most beneficial process in terms of the curcuminoid content (204 mg/g of curcumin) and antioxidant activity of the samples.
... To overcome this problem, we focused on the deketene curcumin analog, GO-Y022. GO-Y022 could be generated by the pyrolysis of curcumin, which occurs during the heating process in cooking curry (31). GO-Y022 has a strong antitumor effect and induces G2 arrest in melanoma cells (31). ...
... GO-Y022 could be generated by the pyrolysis of curcumin, which occurs during the heating process in cooking curry (31). GO-Y022 has a strong antitumor effect and induces G2 arrest in melanoma cells (31). In gastric tumor cell lines, the average IC50 of GO-Y022 is 5-fold lesser than that of curcumin (12). ...
Pyrolyzed deketene curcumin GO-Y022 prevents carcinogenesis in a gastric cancer mouse model. However, it is still less clear if GO-Y022 affects tumor-induced immune suppression. In this study, we found that GO-Y022 inhibited Treg generation in the presence of transforming growth factor beta 1 (TGF-β). However, GO-Y022 showed less impact on Foxp3⁺ Tregs in the gastric tumor microenvironment. Gastric tumor cells produce a large amount of L-lactate in the presence of GO-Y022 and diminish the inhibitory role of GO-Y022 against Treg generation in response to TGF-β. Therefore, naïve CD4⁺ T cells co-cultured with GO-Y022 treated gastric tumor cells increased Treg generation. GO-Y022-induced tumor cell death was further enhanced by 2-deoxy-d-glucose (2DG), a glycolysis inhibitor. Combination treatment of GO-Y022 and 2DG results in reduced L-lactate production and Treg generation in gastric tumor cells. Overall, GO-Y022-treatment with restricted glucose metabolism inhibits gastric tumor cell survival and promotes anti-tumor immunity.
... 114 Dahmke et al. reported that "deketene curcumin" shows better therapeutic effects than curcumin on melanoma cells. 115 This form of curcumin could induce toxicity in B78H1 melanoma cells that finally lead to G2 arrest. Their results confirmed that deketene curcumin can be used as an anti-cancer agent that possesses better bioavailability than curcumin. ...
... Their results confirmed that deketene curcumin can be used as an anti-cancer agent that possesses better bioavailability than curcumin. 115 ...
Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic, and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g. BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin. This article is protected by copyright. All rights reserved.
... It is worth mentioning that, in addition to vanillin, feruloyl acetone (FER) is another intermediate product resulting from the cleavage of the α,β-unsaturated bridge of curcumin. 14 Another study suggested that the proportion of degraded curcumin transformed into FER, when heated at 150°C for 2 h under either alkaline or acidic conditions, was up to 28.8 and 20.6%, respectively. It was proposed that FER could be the major transformation product of curcumin. ...
Some thermal degradants of curcuminoids have demonstrated moderate health benefits in previous studies. Feruloyl acetone (FER), recently identified as a thermal degradant of curcumin, has been previously associated with anticancer and antioxidative effects, yet its other capabilities remain unexplored. Moreover, earlier reports suggest that methoxy groups on the aromatic ring may influence the functionality of the curcuminoids. To address these gaps, an animal study was conducted to investigate the antiobesity effects of both FER and its demethoxy counterpart (DFER) on mice subjected to a high-fat diet. The results demonstrated the significant prevention of weight gain and enlargement of the liver and various adipose tissues by both samples. Furthermore, these supplements exhibited a lipid regulatory effect in the liver through the adiponectin/AMPK/SIRT1 pathway, promoted thermogenesis via AMPK/PGC-1α activation, and positively influenced gut-microbial-produced short-chain fatty acid (SCFA) levels. Notably, DFER demonstrated superior overall efficacy in combating obesity, while FER displayed a significant effect in modulating inflammatory responses. It is considered that SCFA may be responsible for the distinct effects of FER and DFER in the animal study. Future studies are anticipated to delve into the efficacy of curcuminoid degradants, encompassing toxicity and pharmacokinetic evaluations.
... Due to this difference in function, distinct PDBs were utilized for the comparative study. To evaluate the effectiveness of these compounds, they selected the best poses and calculated MolDock scores, H-bonding, re-rank scores, and steric scores between the breast cancer proteins and the ligands (DKC derivatives and the four drugs) [28]. ...
Breast cancer, a global health concern claiming approximately 685,000 lives in 2020, necessitates continual advancements in therapeutic strategies. Estrogen and aromatase play pivotal roles in hormone-responsive breast cancer, with 80% of patients exhibiting estrogen receptor-positive tumors. Aromatase inhibitors (AIs), notably non-steroidal inhibitors like anastrozole and letrozole, have significantly improved outcomes, yet challenges persist, including side effects. This review focuses on recent developments in AIs, exploring xanthone derivatives, imidazole derivatives, and curcumin derivatives as potential inhibitors of aromatase. Molecular docking studies, employing Auto Dock and other tools, reveal the binding affinities and interactions of these compounds with the aromatase enzyme. Among xanthones, Erythrommone emerges as a potent inhibitor, holding promise for clinical trials. Imidazole derivatives, synthesized through the Debus-Radziszewski reaction, demonstrate anticancer potential, with compounds like 1a exhibiting superior efficacy against MCF7 cells. ADME-Tox analyses indicate promising drug-likeness but reveal potential mutagenic effects and environmental impacts. Curcumin derivatives, particularly 1,5-diaryl-1,4-pentadien-3-ones, present alternatives to address curcumin's bioavailability challenges. A study of 25 compounds (DKC) identifies DKC-10 as a potent inhibitor, outperforming established breast cancer drugs in terms of binding affinity and interactions with aromatase and ERα+ receptors. These findings underscore the importance of exploring diverse chemical structures in developing AIs, paving the way for more effective and well-tolerated therapeutics. The integration of computational techniques, such as molecular docking studies, accelerates drug discovery by predicting interactions at the molecular level. Overall, this comprehensive review provides valuable insights into the evolving landscape of aromatase inhibitors, offering a roadmap for future research and the development of advanced breast cancer therapeutics.
... Furthermore, studies have revealed that these compounds decrease mTOR and AKT expression and this concept can be used as a probable target for the treatment of skin cancer [16]. Curcumin analogues explored for treating skin cancer are DMC [17], deketene curcumin [18], diarylpentanoid derivatives of curcumin [19], DM-1 [20], BDMC and 1,7-bis (4hydroxyphenyl)21,4,6-heptatrien-3-one (BHPHTO) [21] (figure 1). However, certain limitations such as rapid metabolization, low bioactive absorption, low targeting efficacy, poor bioavailability and pharmacokinetics, physicochemical instabilities, limited skin permeation, low aqueous solubility, and intrinsic dissolution rate restrict the use of curcumin in skin cancer therapy [22]. ...
Skin cancer refers to any malignant lesions that occur in the skin and are observed predominantly in populations of European descent. Conventional treatment modalities such as excision biopsy, chemotherapy, radiotherapy, immunotherapy, electrodesiccation, and photodynamic therapy induce several unintended side effects which affect a patient’s quality of life (QOL) and physical well-being. Therefore, spice-derived nutraceuticals like curcumin, which are well tolerated, less expensive, and relatively safe, have been considered a promising agent for skin cancer treatment. Curcumin, a chemical constituent extracted from the Indian spice, turmeric, and its analogues has been used in various mammalian cancers including skin cancer. Curcumin has anti-neoplastic activity by triggering the process of apoptosis and preventing the multiplication and infiltration of the cancer cells by inhibiting some signalling pathways and thus subsequently preventing the process of carcinogenesis. Curcumin is also a photosensitizer and has been used in PDT. The major limitations associated with curcumin are poor bioavailability, instability, limited permeation into the skin, and lack of solubility in water. This will constrain the use of curcumin in clinical settings. Hence, developing a proper formulation that can ideally release curcumin to its targeted site is important. So, several nanoformulations based on curcumin have been established such as nanogels, nanoemulsions, nanofibers, nanopatterned films, nanoliposomes and nanoniosomes, nanodisks, and cyclodextrins. The present review mainly focuses on curcumin and its analogues as therapeutic agents for treating different types of skin cancers. The significance of using various nanoformulations as well non-nanoformulations loaded with curcumin as an effective treatment modality for skin cancer is also emphasized.
... Studies conducted in recent years have confirmed that various methods of the thermal processing of turmeric cause changes in the content of the active constituents and thus affect its antioxidant and anticancer activity [52,63,64]. Dahmke et al. [65] confirmed that the traditional way of frying turmeric before consumption, practiced for centuries by Indians, leads to the formation of derivatives with an exceptionally high anticancer activity. Even if there are many studies regarding the influence of thermal processing on the changes in the composition and biological activity in the ginger rhizome, so far no discoveries have been made proving that the heat treatment of ginger rhizomes can contribute to the synthesis of completely new derivatives with increased biological activity. ...
Ginger (Zingiber officinale Rosc.) is a spice, medicinal and cosmetic plant that has been known for centuries. It can be used in dried, fresh, marinated or candied form, and is also an essential ingredient in well-known curry blends. Ginger rhizomes are often freeze-dried as the first step in the preparation of the raw material. Many studies have proved that the composition and biological activity of ginger changes due to thermal processing. Therefore, the aim of the review was to summarize the scientific results on the impact of traditional and unconventional methods of the heat treatment of ginger rhizomes and their influence on the antioxidant and other selected biological activities of the plant. The review of the available scientific data is inconclusive, and it is hard to state unequivocally whether the thermal treatment of the raw material increases or decreases biological activity. Based on the presented literature review, it can be concluded that traditional cooking and microwave processing in general decrease the antioxidant activity of the ginger rhizome, whereas frying, autoclaving, blanching or traditional drying in the sun mostly lead to a significant increase in ginger activity. Interesting data were presented in the works describing the freeze-drying process during which the antioxidant potential of ginger increased.
... 16 Other degradation products include deketene curcumin, and other dimerization end-products. 10,17,18 Deketene curcumin has greater hydrophilicity than curcumin and it enhances the bioactivity of curcumin. 17 Bicyclopentadione is the major end product formed during the spontaneous autoxidation of curcumin. ...
Epidermal growth factor receptor (EGFR), a member of ErbB family of receptor tyrosine kinases, is reportedly overexpressed in various types of human malignancies. Curcumin, a derived phytochemical compound, has demonstrated antiproliferative effects in various cancer cell lines. Since curcumin degrades into different bioactive compounds, attention has been drawn to analyze if these degradation products are primarily responsible for the observed biological activity of curcumin. In the current work 11 degradation products of curcumin were selected and assessed for their drug likeness, ADME and toxicity properties using a diverse range of advanced computational methods. Binding characteristics of EGFR with these ligand molecules were examined using in silico single ligand molecular docking and multi-ligand simultaneous docking (MLSD) methods. Spiroepoxide, one intermediate product of spontaneous oxidation of curcumin, docked with minimum energy ([Formula: see text]9.123[Formula: see text]kcal/mol) as compared to parent curcumin and co-crystallized Erlotinib inhibitor. Vina score for simultaneously docked autooxidation compounds at the binding site of EGFR, where one ligand was curcumin, was lower than the predicted binding energies of singly docked compounds, thus indicating that curcumin-derived compounds produced by the oxidative pathway do take part along with curcumin in inhibiting EGFR. The best ‘posed’ complex, spiroepoxide bound to EGFR, was chosen for MD simulation to examine the stability of this protein–ligand complex.
... These synthetic C 5 -curcuminoids have shown superior cytotoxicity and a much better pharmacokinetic profile due to higher structural stability compared to curcumin (Liang et al., 2009). Whether C 5 -curcumin is a metabolite of C 7 -curcumin or not, the truncated monocarbonyl curcumin (2) can be synthesized from the dicarbonyl curcumin (1) in a pyrolysis reaction (Dahmke et al., 2014). The reaction was carried out in coconut oil, suggesting that people eating meals containing turmeric from the wok are consuming C 5 -curcumin (2) in a considerable amount per year. ...
Novel series of cyclic C5-curcuminoids 17a-j and 19-22 were prepared as cytotoxic agents and evaluated against human neuroblastoma (SH-SY5Y) or human grade IV astrocytoma (CCF-STTG1) cell lines in low (∼0.1nM - 10nM) concentrations. Among the tested 21 derivatives, 16 displayed potent antiproliferative activity with IC50 values in the low nanomolar to picomolar range (IC50=7.483-0.139 nM). Highly active compounds like N-monocarboxylic derivative 19b with IC50=0.139 nM value against neuroblastoma and N-alkyl substituted 11 with IC50=0.257 nM against astrocytoma proved some degree of selectivity toward non-cancerous astrocytes and kidney cells. This potent anticancer activity did not show a strong correlation with experimental logPTLC values, but the most potent antiproliferative molecules 11-13 and 19-22 are belonging to discrete subgroups of the cyclic C5-curcuminoids. Compounds 12, 17c and 19b were subjected to blood-brain barrier (BBB) penetration studies, too. The BBB was revealed to be permeable for all of them but, as the apparent permeability coefficient (Papp) values mirrored, in different ratios. Lower toxicity of 12, 17c and 19b was observed toward primary rat brain endothelial cells of the BBB model, which means they remained undamaged under 10 µM concentrations. Penetration depends, at least in part, on albumin binding of 12, 17c and 19b and the presence of monocarboxylic acid transporters in the case of 19b. Permeation through the BBB and albumin binding, we described here, is the first example of cyclic C5-curcuminoids as to our knowledge.
... There exists little information about the production of degradation products of curcumin and their kinetics at higher temperatures. One of the studies reported formation of deketene curcumin (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) showing a greater anti-cancer activity than curcumin (Dahmke et al., 2014). Vanillin, 4-vinyl guaiacol and ferulic acid have shown to be formed by heating curcumin at 453 K (Esatbeyoglu et al., 2015). ...
The objective of this work was to study kinetics of thermal degradation of curcumin in ambient–1023K range and identify degradation products by GC-MS. No weight loss was observed up to ∼470K and two major weight losses occurred beyond this. Sixteen degradation products were identified by GC-MS. Pharmacological properties, including LD50, LC50, gastrointestinal absorption, blood brain barrier permeation and effect on cytochromes, of the products were calculated using standard software. The LD50 values indicated that the degradation products are more toxic than curcumin. All the decomposition products, except 2-methyl-6-(4-methylphenyl)-hept-2-en-4-one, have the potential to cross the blood-brain barrier that can affect brain functions. Twelve of the compounds showed the potential to inhibit the metabolism of xenobiotics and all the compounds appeared to be non-inhibitors of CYP2C9 and CYP3A4 in contrast to curcumin. Thus, this study suggests that the food materials containing curcumin when heated beyond 470K will produce toxic substances.
... Here, Table 5 represents the MolDock score, H-bonding, re-rank score, and steric score between protein of breast cancer and ligand (DKC derivatives and 4 drugs). In addition to this, through literature it was confirmed that ligands (DKC-10, DKC-20, and DKC-21 for Erα +) which are exhibited binding affinity less than −150 kcal/mol would be regarded as a more effective inhibitor [40][41][42][43][44][45][46][47][48]. In this study, 3 deketene curcumin derivatives (DKC-10, DKC-20, and DKC-21) out of 25 Tables 8 and 9 and Figs. 9 and 10. ...
Regardless of many extensive studies, hormonal-based breast cancer is the most common cause of cancer-related mortality of females worldwide. Indeed, estrogen receptor-positive (ER +) is the communal subtype in breast cancer. To treat this, three types of medications are typically used: selective estrogen receptor modulators (SERMs), selective estrogen receptor down modulators (SERDMs), and aromatase inhibitors (AIs), all of which directly interact with the activation of the estrogen signaling pathway and its formation. Despite their effectiveness, the development of new treatments is required since clinical efficacy is restricted owing to resistance. As a result, in silico studies for drug discovery are booming over the decades because of their affordability and less time-consuming features. Here, 25 deketene curcumin derivatives have been selected for docking studies through MVD software over the positive type of breast cancer through both the treatment hosts Erα + receptor and aromatase. DKC compounds are used because they have several pharmacological uses, including anti-cancer, anti-diabetic, anti-viral, anti-fungal, and anti-bacterial properties. Moreover, an ADME study was carried out for DKC derivatives that reveal the optimum drug-likeness profile. From 25 derivatives, the results showed a better MolDock score, hydrogen bonding, and steric interaction between compounds DKC-10, DKC-20, and DKC-21 with Erα + and aromatase. Although the study was done on both the treatable path hosts, better results were obtained with Erα + as an antagonist. Therefore, it is proposed that three selected DKC derivatives would be better therapeutic agents against breast cancer.
... Although curcumin (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) provides lots of medicinal applications but, there are some drawbacks of curcumin such as the less bioavailability of orally administered curcumin, it shows minimal buffer and plasma stability, and other factors. Therefore, Modification in curcumin is required one of the potent compound is deketene curcumin (1, 5-bis (4-hydroxy-3-methoxyphenyl)-1, 4-pentadiene-3-one) [10]. Henceforth, This particular derivative of curcumin (deketene curcumin) has been chosen for simulation against COVID-19. ...
p>World Health Organization (WHO) reveals total number of coronavirus cases are 5,684,802 and 352,225 deaths till today worldwide. Coronavirus instances are nevertheless surging due to its speedy spreading through infected patients. Therefore, in order to find potent vaccine almost every researcher is doing hard work to find it. However, until today there is not any availability of effective vaccine or drug for the treatment of COVID-19. In this case, the computational approach is the good choice to identify effective drugs and could be very useful due to its low cost, less error and less time consumption. Here, Deketene curcumin has taken for docking study because of its lots of biological applications such as antiviral, antimicrobial, anti-inflammatory, antioxidant, antibiotic, and to a name of few, it is a derivative of curcumin. In this study, five main protease crystallized COVID-19 structures (PDB ID: 6LU7, 5R7Z, 5R7Y, 5R80, 5R81) have been taken for simulation against deketene curcumin. Required procedure for this in silico study done through Molegro virtual docker (MVD) and Molegro Molecular Viewer (MMV) used for visualization. The results showed H-bonding and steric interaction between Deketene Curcumin with COVID-19 (PDB ID: 6LU7, 5R7Z, 5R7Y, 5R80, 5R81). Moldock scores of Deketene Curcumin Observed -134.198 kcal/mol, -151.972 kcal/mol, -109.224 kcal/mol, -140.741 kcal/mol and -126.562 kcal/mol with PDB Id 6LU7, 5R7Z, 5R7Y, 5R80 and 5R81 respectively. As per our results, it can be say that Deketene Curcumin has effective as a lead compound to find new antiviral drug candidates against COVID-19 for possible medicinal agent.</p
... 12 In fact, diketene curcumin, as another naturally found degradant in curcumin-containing cuisine, was suggested to exhibit anti-cancerogenic activity against B78H1 melanoma cells, as a result of cell cycle G2 arrest. 13 In comparison, the study by Feng and Liu (2011) is the only study that discussed demethoxy-feruloylacetone (DFER) as a dihydroxy-feruloylacetone or 6-(m,pdihydroxyphenyl)-5-hexene-2,4-dione. 11 Both FER and DFER previously exhibited antioxidation activity, and the result showed that there were faster decrements when scavenging DPPH radicals rather than galvinoxyl radicals, indicating that FER and DFER might have a higher anti-oxidation activity than their precursor. ...
Feruloylacetone (FER) is a natural degradant of curcumin after heating, which structurally reserves some functional groups of curcumin. It is not as widely discussed as its original counterpart in previous studies and, therefore, its anti-cancer efficacy is investigated herein. This study focuses on the suppressive effect of FER on colon cancer, as the efficacious effect of curcumin on this typical cancer type has been well evidenced. In addition, demethoxy-feruloylacetone (DFER) was applied to compare the effect that might be brought on by the structural differences of the methoxy group. It was revealed that both FER and DFER inhibited the proliferation of HCT116 cells, possibly via suppression of the phosphorylated mTOR/STAT3 pathway. Notably, FER could significantly repress both the STAT3 phosphorylation and protein levels. Furthermore, both samples showed the capability of arresting HCT116 cells at the G2/M phase via the activation of p53/p21 and upregulation of cyclin-B. In addition, ROS elevation and changes in mitochondrial membrane potential were revealed, as indicated by p-atm elevation. The apoptotic rate rised to 36.9% and 32.2% after being treated by FER and DFER, respectively. In summary, both compounds exhibited an anti-cancer effect, and FER showed a greater pro-apoptotic effect, possibly due to the presence of the methoxy group on the aromatic ring.
... Although curcumin (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) provides lots of medicinal applications but, there are some drawbacks of curcumin such as the less bioavailability of orally administered curcumin, it shows minimal buffer and plasma stability, and other factors. Therefore, Modification in curcumin is required one of the potent compound is deketene curcumin (1, 5-bis (4-hydroxy-3-methoxyphenyl)-1, 4-pentadiene-3-one) [10]. Henceforth, This particular derivative of curcumin (deketene curcumin) has been chosen for simulation against COVID-19. ...
World Health Organization (WHO) reveals total number of coronavirus cases are 5,684,802 and 352,225
deaths till today worldwide. Coronavirus instances are nevertheless surging due to its speedy spreading
through infected patients. Therefore, in order to find potent vaccine almost every researcher is doing hard
work to find it. However, until today there is not any availability of effective vaccine or drug for the treatment of
COVID-19. In this case, the computational approach is the good choice to identify effective drugs and could
be very useful due to its low cost, less error and less time consumption. Here, Deketene curcumin has taken
for docking study because of its lots of biological applications such as antiviral, antimicrobial,
anti-inflammatory, antioxidant, antibiotic, and to a name of few, it is a derivative of curcumin. In this study, five
main protease crystallized COVID-19 structures (PDB ID: 6LU7, 5R7Z, 5R7Y, 5R80, 5R81) have been taken
for simulation against deketene curcumin. Required procedure for this in silico study done through Molegro
virtual docker (MVD) and Molegro Molecular Viewer (MMV) used for visualization. The results showed
H-bonding and steric interaction between Deketene Curcumin with COVID-19 (PDB ID: 6LU7, 5R7Z, 5R7Y,
5R80, 5R81). Moldock scores of Deketene Curcumin Observed -134.198 kcal/mol, -151.972 kcal/mol,
-109.224 kcal/mol, -140.741 kcal/mol and -126.562 kcal/mol with PDB Id 6LU7, 5R7Z, 5R7Y, 5R80 and 5R81
respectively. As per our results, it can be say that Deketene Curcumin has effective as a lead compound to
find new antiviral drug candidates against COVID-19 for possible medicinal agent.
... In spite of this, some studies have suggested the creation of new metabolites and other new derivatives of volatile components in thermal processing (Jolad et al. 2005;Höferl et al. 2015). Dahmke et al. (2014) explained an uplifted anticancer potential of turmeric tubers that were initially thermally processed. ...
The acceptability of food is significantly increased by the addition of herbs and spices. Moreover, herbs and spices also improve the shelf life of food, delay its oxidation, and may even impart health‐promoting properties to the consumers. Herbs and spices may be added in food in different forms which may include cutting, slicing, grinding, blanching, boiling, roasting, etc. The present chapter discusses various techniques used in processing of herbs and spices for their utilization in food.
... Other DAPs with a similar structure as MS13 such as FLLL-11 and GO-Y022 were observed to inhibit cell viability of colon (HCT116, HT29, and SW480) [65], pancreatic (PANC-1, BXPC-3, MIA-PACA-2, ASPC-1, and HPAC) [65] and gastric (KATO III, GCIY, H-111-TC, and SH-10-TC) cancer cell lines at a much lower dose than curcumin [66]. Besides, a product of curcumin pyrolysis during cooking and heating, known as "deketene curcumin" was observed to share similar structure as MS13, also demonstrated significant reduction of cell viability in melanoma cells compared to curcumin [67]. As such, this highlights the potency of curcumin analogue with 5-bis(4-hydroxy-3-methoxyphenyl)-1, 4-pentadiene-3-one structure in inhibiting cancer cell viability. ...
The cytotoxic and apoptotic effects of turmeric (Curcuma longa) on colon cancer have been well documented but specific structural modifications of curcumin have been shown to possess greater growth-suppressive potential on colon cancer than curcumin. Therefore, the aim of this study is to identify the anti-cancer properties of curcumin analogue-MS13, a diarylpentanoid on the cytotoxicity, anti-proliferative and apoptotic activity of primary (SW480) and metastatic (SW620) human colon cancer cells. A cell viability assay showed that MS13 has greater cytotoxicity effect on SW480 (EC50: 7.5 ± 2.8 µM) and SW620 (EC50: 5.7 ± 2.4 µM) compared to curcumin (SW480, EC50: 30.6 ± 1.4 µM) and SW620, EC50: 26.8 ± 2.1 µM). Treatment with MS13 at two different doses 1X EC50 and 2X EC50 suppressed the colon cancer cells growth with lower cytotoxicity against normal cells. A greater anti-proliferative effect was also observed in MS13 treated colon cancer cells compared to curcumin at 48 and 72 h. Subsequent analysis on the induction of apoptosis showed that MS13 treated cells exhibited morphological features associated with apoptosis. The findings are also consistent with cellular apoptotic activities shown by increased caspase-3 activity and decreased Bcl-2 protein level in both colon cancer cell lines. In conclusion, MS13 able to suppress colon cancer cell growth by inhibiting cell proliferation and induce apoptosis in primary and metastatic human colon cancer cells.
... The antitumor activity of both Cur and PEG-MSNPs-Cur against HepG2 and HeLa cells was assessed using a WST-1 assay and an inverted light microscope (S1) [40]. ...
This study aims to synthesize smart mesoporous silica nanocarrier for curcumin (Cur) as a nutraceutical anticancer agent. Multifunctional PEG-MSNPs-Cur were synthesized to enhance curcumin bioavailability for the purpose of preventing and treating cancer. It can also serve as auto-fluorescence probe for molecular imaging (image guided therapy).
The prepared nanocarrier has been characterized using transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FTIR), Dynamic light scattering (DLS) and zeta potential.
In vitro, the antitumor activity of PEG-MSNPs-Cur and Cur was investigated on two human cancer cell lines: liver cancer (HepG2) and cervical cancer (HeLa). Compared with free-Cur, PEG-MSNPs-Cur showed higher cellular uptake and significant cytotoxicity against HepG2 and HeLa cells. Furthermore, PEG-MSNPs-Cur-treated HepG2 cells exhibited marked cell cycle arrest at G2/M compared to free-Cur-treated cells.
In vivo, cancer chemoprevention and therapeutic efficacy of PEG-MSNPs-Cur as well as Cur, have been evaluated using two treatment protocols: Tumor Chemoprevention Protocol (TCP) and Tumor Reduction Protocol (TRP). The results demonstrated that TCP exhibited high therapeutic efficacy over TRP.
The toxicity of PEG-MSNPs-Cur were assessed by serum biochemical analysis and histopathological examination for certain vital body organs to address the biosafety issue of PEG-MSNPs-Cur.
The integrated results indicated that smart multifunctional MSNPs greatly enhanced curcumin bioavailability. PEG-MSNPs-Cur offered pH-triggered drug release in an acidic pH (tumor microenvironment). Additionally, PEG-MSNPs-Cur is utilized as self-fluorescence probe that allow their tracing in the cells without the need of dyes. PEG-MSNPs-Cur could be effectively used as a safe chemopreventive and therapeutic agent.
... However, curcuminoids readily degrade when heated, and cooking like boiling and roasting will result in the degradation of curcuminoids to a great extent (5)(6)(7)16). The degradation products of curcumin after cooking also possess biological properties similar to the parent compound (25,26). Curcuminoids were reported to have neuroprotective effects via reducing oxidative stress (27). ...
Curcuminoids, as the main ingredient of turmeric, are popularly used in food additives and condiments, and are widely accepted to be beneficial for human health for their antioxidant activity. However, curcuminoids are highly susceptible in terms of thermal-induced degradation, and curry is usually boiled, roasted, or fried in the use of food additives and condiments. Thus, it is interesting to explore the effect of cooking on the antioxidant activity of curcuminoids. In the present study, the total antioxidant capacity (T-AOC) of cooked curcuminoids (boiled curcuminoids, roasted curcuminoids, and fried curcuminoids) processed through three heating conditions, and their protective effects against oxidative damage to rat pheochromocytoma (PC12) cells, a well-established neuronal model, were evaluated. It was found that cooking slightly lowered the T-AOC of curcuminoids, with boiled curcuminoids being relatively stronger than roasted curcuminoids, and fried curcuminoids being the weakest form. Both boiled and roasted curcuminoids could significantly improve cell viability, mitigate intracellular accumulation of reactive oxygen species and reduce malondialdehyde activity, reduce caspase-3 and caspase-9 protein expression, and increase superoxide dismutase activity of PC12 cells compared with the control group. In comparison with parent curcuminoids, the protective effects of cooked curcuminoids got relatively lower overall, with boiled curcuminoids being relatively stronger than roasted curcuminoids. In conclusion, the cooked curcuminoids, including boiled and roasted forms, still have antioxidant and neuroprotective activity.
... This activity was recorded in heterocyclic analogs containing 2-chloro or 2-phenoxyquinoline [44], symmetrical hexamethoxydialpentadienones [45], allylated mono-carbonyl curcumin analogs (MACs), which have dihydrothiopyran-4-one [46], T83 (1E,6E)-4-(3-hydroxy-4-methoxybenzylidene)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,6-diene-3,5-dione [47], dehydrozingerone [48], B63 a 1,5-bis(2-methoxyphenyl)-penta-1,4-dien-3-one [49], resveratrol-curcumin hybrids in which hydroxy groups replaced by methoxy groups [50], curcumin mimics with an additional bridged phenyl ring in conjugation [51], diketene curcumin [52] then the target of the molecule is to disrupt the cell cycle in the G2/M phase. Respectively structures like (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones containing a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings and structurally similar to the enol-tautomer of curcumin [53], (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones containing two identical nitrogen-containing terminal heteroaromatic rings and para pyridyls and quinolin-4-yl rings which serve as favorable heteroaromatic rings [54], bisdimethoxy (BDMC) [55], benzylidine cyclohexanone derivatives with non-polar groups (2,6-bis benzylidine cyclohexanone analogs) arrest the cell cycle in the G 0 /G1 S1). ...
Introduction: Curcumin (Diferuloylmethane) is a natural phenolic compound, which belongs to the curcuminoid family, presenting pleiotropic activity and low bioavailability. A lot of recent research is focused on the design and synthesis of curcumin analogs as antiproliferative and anti-inflammatory agents improving the bioavailability and target selectivity. Their structural characteristics and functional groups seem to define the extent of the biological activity.
Areas covered: Publications (2008–2018), describing curcumin analogs and curcumin derivatives are analyzed. Structural characteristics, functional groups, modelling studies, structure activity relationships, biological evaluation in vitro/in vivo as antiproliferative and anti-inflammatory agents are included. Furthermore, a wide range of biological results derived from different targets are also summarized.
Expert opinion: Several curcumin analogs and derivatives appear to have a high biological impact as well as promising antiproliferative and anti-inflammatory activities. Their clinical evaluation will be critical to assess therapeutic utility. Compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.
... Pyrolysis of curcumin at high temperatures with and without coconut fat or olive oil, has been shown to cause degradation, leading to more polar products including deketene curcumin which has been reported to have cytotoxic activity in mouse melanoma cells superior to curcumin itself. [30] We chemically synthesized a standard of this degradation product but found no evidence of its presence in the food samples using a HPLC-UV method [22] with detection at both 426 and 280 nm (data not shown). However, the methods were not optimized for this particular derivative and we did not search for other potential degradation products of curcumin, so it is conceivable that they were present in low amounts but were not detected using our assay. ...
Scope
Curcumin, (from turmeric), has been extensively investigated for potential beneficial properties in numerous diseases. Most work has focussed on supra‐dietary concentrations/doses that would necessitate curcumin supplementation. However, much evidence instigating curcumin research is underpinned by epidemiological data based on low dietary intake via turmeric consumption.
Methods and Results
Here, we describe a novel, highly sensitive liquid chromatography‐electrospray ionization‐mass spectrometry (LC‐ESI‐MS/MS) method for detection of curcuminoids. Assay sensitivity was demonstrated in a pilot pharmacokinetic volunteer study following ingestion of foodstuffs containing a standardised mass of turmeric, representative of daily consumption by certain South Asian populations. Free parent curcumin was detectable in plasma from one individual, reaching maximal plasma concentrations (Cmax) of 3.2 nM. Curcumin conjugates were detected in all volunteers; Cmax for curcumin glucuronide was 47.6 ± 28.5 nM 30 minutes post‐food, whilst Cmax for demethoxycurcumin glucuronide and curcumin sulfate was ∼2 nM. Curcumin and its major metabolites persisted in plasma for at least 8 hours.
Conclusion
Despite poor absorption and rapid conjugation, dietary intake of standard culinary turmeric within complex food matrices furnished human plasma with detectable levels of curcuminoids. Whether sustained low systemic concentrations of these non‐nutritive, biologically active, dietary components may have pharmacological activity for human health benefit, warrants further research.
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... This family is composed of 70-80 species of rhizomatous annual or perennial herbs. The concurrence of a high consumption of turmeric in Asian countries and a low incidence of cancer suggest its role in chemoprevention (3,4). ...
Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways. Curcumin is a promising molecule for the prevention and treatment of cancer.
... In the case of ginger these are shogaols and other new derivatives of volatile components [10,16]. Furthermore, Dahmke and co-investigators [17] described an elevated anticancer potential of turmeric tubers that were initially thermally processed. These data may explain the increase in some biological activities of natural products present in the Zingiberaceae family, but detailed mechanisms of biotransformation are still not known. ...
Zingiber officinale (Zingiberaceae) is a common spice and a medicine widely cultivated in tropical and subtropical climate around the globe, which contains both precious polyphenols and terpenes in its extracts. The ubiquity of ginger in a variety of foods encouraged the authors to assess the influence of thermal processing and digestion of the plant material on its antioxidant capacity. The obtained results of DPPH assay showed marked differences in the antioxidant potential of the processed samples, in comparison with fresh ginger rhizomes. Autoclave and microwave heating procedures were found to evoke the mildest decomposition of the antioxidants and increase the antioxidant capacity of the plant (from IC50 of 210±10 for a fresh rhizome to ca 160±16 μg/mL for the former, and to 150±18 for the latter technique), whereas frying and boiling for different durations significantly deteriorated the antiradical potential up to IC50 = 940±36 μg/mL. Mouth and stomach digestion decreased the antioxidant potential of the extracts even to ca. 1000±47 μg/mL. A protective role of saliva towards the antioxidant compounds against hydrochloric acid and pepsin activities has been proven. A marked deterioration in antioxidant capacity in digested rhizomes may shed new light on the actual absorption of consumed polyphenols with food products.
... Curcumin (CUR) or bis(4-hydroxy-3-methoxyphenyl)-1,6-hept- adiene-3,5dione (Fig. 1a), an orange polyphenol found in turmeric, is a very valuable medicinal plant with health benefits including anti-inflammation (Julie & Jurenka, 2009), anti-microbial (De et al., 2009), anti-oxidant (Menon & Sudheer, 2007) and anti-cancer (Yallapu, Jaggi, & Chauhan, 2010) activity. It has been revealed that curcumin, an Indian traditional dietary ingredient, is responsible for the reduction of colon, lung and prostate cancer in India (Dahmke, Boettcher, Groh, & Mahlknecht, 2014). Clinical data have shown that curcumin inhibits the accumulation of triglycerides in rat liver (Shoji et al., 2014). ...
... In recent years, however, exceptional examples have proven that covalent-bond-forming compounds can afford promising results in drug development. Very recently, Mahlknecht and coworkers disclosed that C5-curcumin (2), showing superior antitumor activity to curcumin, is formed by pyrolyzing curcumin with coconut fat, suggesting that cooking enhances the anticancerogenic activity of curcumin [22]. Yang and coworkers also reported that C5-curcuminoid has better pharmacokinetic characteristics than curcumin [9]. ...
1,5-Bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (2) was isolated from Curcuma domestica as a curcumin (1)-related compound, which we named C5-curcumin. Intrigued by the potent antitumor activity of C5-curcumin (2)-related 1,5-bisaryl-1,4-pentadiene-3-ones [bis(arylmethylidene)acetones, termed C5-curcuminoids], we previously conducted a structure–activity relationship study of C5-curcuminoids and showed that highly active GO-Y030 [1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one (4)] is the most promising antitumor compound. In this study, a panel of C5-curcuminoids based on GO-Y030, consisting of 30 new and 10 known compounds, was synthesized to elucidate in detail which moiety of GO-Y030 is significant for antitumor activity. The results confirmed that both the cross-conjugated dienone moiety and the 3,5-bis(methoxymethoxy) substituent are important for the antitumor activity.
... Curcumin (CUR) or bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione (Fig. 1a), an orange polyphenol found in turmeric, is a very valuable medicinal plant with health benefits including anti-inflammation (Julie & Jurenka, 2009), anti-microbial (De et al., 2009), anti-oxidant (Menon & Sudheer, 2007) and anti-cancer (Yallapu, Jaggi, & Chauhan, 2010) activity. It has been revealed that curcumin, an Indian traditional dietary ingredient, is responsible for the reduction of colon, lung and prostate cancer in India (Dahmke, Boettcher, Groh, & Mahlknecht, 2014). Clinical data have shown that curcumin inhibits the accumulation of triglycerides in rat liver (Shoji et al., 2014). ...
Curcumin which is an effective component found in turmeric has anti-inflammatory properties and can be used to decrease pains and inflammations of body joints in patients suffering from rheumatism. Unfortunately this substance due to its substantial hydrophobicity levels, does not offer expected Therapeutic features. Thus many works has been aimed at increasing its solubility. In the current project one method which utilizes Cyclodextrin to encapsulate Curcumin is investigated. Cyclodextrin due to its amphiphilic hydrophobicity/hydrophilicity properties, has shown a great ability to form complexes with other hydrophobic materials and produce complex Nano-particles thus the major goal of this project is to use Cyclodextrin and Cyclodextrin-Curcumin Nano-particles formation in order to increase the water solubility of Curcumin. The resulted complex can be adequate substitute for sole Curcumin. In addition to microscopic techniques of detecting formed Nano-particles, one might consider some other alternatives such as NMR, DCS and FTIR analysis as well.
... The safety of diarylpentanoid-type curcumin analogs has been shown in a recent study, and the diarylpentanoid curcumin analog 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4pentadiene-3-one (GO-Y022) has been detected in cooked curry [47]. Thus, some deketone curcumin analogs such as diarylpentanoids may be safe to eat. ...
... The safety of diarylpentanoid-type curcumin analogs has been shown in a recent study, and the diarylpentanoid curcumin analog 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4pentadiene-3-one (GO-Y022) has been detected in cooked curry [47]. Thus, some deketone curcumin analogs such as diarylpentanoids may be safe to eat. ...
Background:
Potent chemotherapy for advanced gastric cancer has not been completely established. Many molecularly targeted therapies are under investigation, but their therapeutic outcomes are not promising because they do not target specific and/or critical targets of gastric carcinogenesis. Although the molecular basis of gastric carcinogenesis remains poorly understood, nuclear localization of β-catenin was observed in approximately 50 % of gastric cancer specimens. Recent studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) contributes to gastric carcinogenesis in a mouse model. A newly synthesized curcumin analog has inhibitory potential against β-catenin and STAT3.
Methods:
Using a transgenic mouse model of gastric cancer in which β-catenin, cyclooxygenase 2, and microsomal prostaglandin E synthase 1 activation is induced, we examined a curcumin analog with the most enhanced potential for treating gastric cancer through oral administration. Inhibition of these targets was demonstrated using microarray and immunohistochemical analyses.
Results:
The curcumin analog GO-Y031 decreased the incidence of gastric carcinogenesis to 54.5 % of that of the control (50.0 % vs 91.7 %, p = 0.043), and tumor size was reduced to 51.6 % of that of the control (1.6 mm vs 3.1 mm, p = 0.03). β-Catenin and STAT3 levels were suppressed to 26.2 % (p = 0.00023) and 44.8 % (p = 0.025), respectively, of those of the control. Moreover, macrophage infiltration was suppressed with GO-Y031.
Conclusion:
β-Catenin and STAT3 can be pharmacologically inhibited in vivo with a curcumin analog, which effectively inhibits β-catenin and STAT3.
... A study by Suresh et al. [42] suggested that during domestic cooking the chemical structure of curcumin was degraded to ferulic acid, vanillin and vanillic acid. On the other hand, Dahmke [43] reported that cooking enhances the anticancer activity of curcumin by pyrolytic formation of so-called deketene curcumin (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one). Taken together the thermal effects appear to alter the chemical structure of curcumin and in the former study by Suresh et al. the three metabolites that are formed have also been reported elsewhere in the literature [44,45] to exhibit antioxidant activities irrespective of the pyrolytic formation as proposed in the latter study. ...
Curcumin is a major constituent of the turmeric plant Curcuma longa, a member of the Zingiberaceae family, which is cultivated in India, most parts of Southeast Asia, Asia and other parts of the world. Curcumin has been shown to afford a wide range of pharmacological activities encompassing antioxidative, anti-inflammatory, antibacterial, antifungal, antiviral, antiproliferative, proapoptotic and anti-atherosclerotic effects as well as medicinal benefits against neurodegenerative diseases, arthritis, allergy, inflammatory bowel disease, nephrotoxicity, AIDS, psoriasis, diabetes, multiple sclerosis, cardiovascular disease and lung fibrosis. Moreover, curcumin could suppress inflammatory cytokines as well as suppress various target proteins in cancer cell lines. Owing to its multi-faceted health benefits, curcumin has been used as health supplements as well as natural remedy while several clinical trials are under way to investigate its potential therapeutic usage. This chapter discusses the origins of curcumin’s biological activities in light of its structure-activity relationship. The structure of curcumin is comprised of the central 1,6-heptadiene-3,5-dione bearing two terminal phenolic rings. Structural modification of this compound alters its biological activities either by affecting its selectivity, specificity or potency. Understanding of such structure-activity relationship may provide the impetus for further expanding its biological activity repertoire. Although it is an ambitious task to review the current state-of-the-art on the structure-activity relationship of curcumin, it should be mentioned that it is impossible for this chapter to provide a comprehensive account but rather a representative overview is given herein.
... Curcumin (CUR) or bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione (Fig. 1a), an orange polyphenol found in turmeric, is a very valuable medicinal plant with health benefits including anti-inflammation (Julie & Jurenka, 2009), anti-microbial (De et al., 2009), anti-oxidant (Menon & Sudheer, 2007) and anti-cancer (Yallapu, Jaggi, & Chauhan, 2010) activity. It has been revealed that curcumin, an Indian traditional dietary ingredient, is responsible for the reduction of colon, lung and prostate cancer in India (Dahmke, Boettcher, Groh, & Mahlknecht, 2014). Clinical data have shown that curcumin inhibits the accumulation of triglycerides in rat liver (Shoji et al., 2014). ...
Curcumin exerts some of its biological effects via degradation products formed by spontaneous oxidation at physiological, i.e., weakly basic, pH. Here, we analyzed products formed by dry heating of curcumin in the presence of a basic salt (sodium bicarbonate and others). Under the dry heating conditions employed, curcumin was completely consumed, yielding products entirely different from those obtained by autoxidative degradation in buffer. Bioassay-guided fractionation of the reaction mixture was used to identify and isolate compounds with anti-inflammatory activity in a cell-based assay. This provided two dimers of curcumin, dicurmins A and B, featuring a partly saturated naphthalene core that inhibited lipopolysaccharide-induced activation of NF-κB in RAW264.7 cells. Dicurmin A and B are unusual derivatives of curcumin lacking key functional moieties yet exhibit increased anti-inflammatory activity. The process of dry heating of polyphenols in the presence of a basic salt can serve as a novel approach to generating bioactive compounds.
Curcumin has long been recognized for its anti-inflammatory properties. An antitumor effect has been recently reported in curcumin and clinical trials are being conducted. However, a large amount of required intake to obtain the antitumor effect of curcumin has been regarded as a problem. Therefore, curcumin analogs have been created by many researchers to enhance the effects of curcumin. We have synthesized >50 curcumin analogs and revealed greater growth suppression of various tumor cells with mono-carbonyl analogs than curcumin. Mechanistically, mono-carbonyl analogs inhibited transcriptional activity (e.g., nuclear factor kappa B, signal transducer, and activator of transcription 3) or activated caspase-3. Additionally, mono-carbonyl analogs of curcumin control tumor cell metabolism. Herein, we summarize the current knowledge about mono-carbonyl curcumin analogs and discuss their potential clinical applications.
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Curcumin with medicinal value should possess good bioavailability and stability. Unfortunately, the bioavailability of curcumin is less and its stability depends on the medium. After intake of curcumin, it undergoes metabolism to form metabolites, which are bioactive and show better bioavailability than curcumin. Hence, the disadvantages of curcumin can be overcome by the formation of its synthetic derivative. In this review paper, the derivatives of curcumin namely tetrahydrocurcumin, hexahydrocurcumin, octahydrocurcumin, deketene curcumin and dimethoxycurcumin are discussed. The diketo group, diene moiety and ortho-methoxy phenolic groups present in curcumin influence its properties. Curcumin undergoes degradation in alkaline and non-polar mediums, mainly because of its property to exhibit keto-enol tautomerism, which is further enhanced due to the presence of diene moiety and ortho-methoxy phenolic groups. If the keto-enol tautomerism is inhibited by its derivatization, then its stability is improved. This is especially true in the case of hexahydrocurcumin, octahydrocurcumin and deketene curcumin which do not possess an active methylene group. Although tetrahydrocurcumin undergoes keto-enol tautomerism, the degradation of enol tautomer is prevented due to the absence of diene moiety. The activities of curcumin are medium dependent whereas the activities of hydrogenated derivatives of curcumin and deketene curcumin are medium independent. Dimethoxycurcumin exhibits keto-enol tautomerism and can undergo degradation in alkaline and non-polar mediums at a faster rate than curcumin. The reason is that the strong activating hydroxyl groups in curcumin are replaced by a stronger activating methoxy groups in dimethoxycurcumin. On the other hand, in acidic and polar mediums, the rate of beneficial activities of dimethoxycurcumin is more than curcumin. Also, the bioavailability of the above-mentioned derivatives of curcumin is more than curcumin.
Feruloylacetone (FER) is a natural degradant of curcumin after heating, which structurally reserves some functional groups of curcumin. It is not as widely discussed as its original counterpart has been previously; and in this study, its anticancer efficacy is investigated. This study focuses on the suppressive effect of FER on colon cancer, as the efficacious effect of curcumin on this typical cancer type has been well evidenced. In addition, demethoxy-feruloylacetone (DFER) was applied to compare the effect that might be brought on by the structural differences of the methoxy group. It was revealed that both FER and DFER inhibited the proliferation of HCT116 cells, possibly via suppression of the phosphorylated mTOR/STAT3 pathway. Notably, FER could significantly repress both the STAT3 phosphorylation and protein levels. Furthermore, both samples showed capability of arresting HCT116 cells at the G2/M phase via the activation of p53/p21 and the upregulation of cyclin-B. In addition, ROS elevation and changes in mitochondrial membrane potential were revealed, as indicated by p-atm elevation. The apoptotic rate rose to 36.9 and 32.2% after being treated by FER and DFER, respectively. In summary, both compounds exhibited an anticancer effect, and FER showed a greater proapoptotic effect, possibly due to the presence of the methoxy group on the aromatic ring.
Curcumin is a phenolic compound produced by some plants, among which Curcuma longa is the reachest in this principal curcuminoid. At elevated temperature curcumin degrades to trans-6-(4′-hydroxy-3′-methoxyphenyl)-2,4-dioxo-5-hexenal, vanillin, ferulic acid and feruloylmethane, however, the formation of feruloyloacetone ((5E)-6-(4-hydroxy-3-methoxyphenyl)hex-5-ene-2,4-dione) in the curcumin degradation process has not been reported yet. As results from experiments, even 28.8% or 20.6% of the degraded curcumin is transformed to feruloyloacetone during 2 h heating of alkaline or acidic curcumin solution, respectively. The structure of the identified feruloyloacetone was confirmed by MS ⁿ , HRMS and NMR data. The presented results are important for food processing as feruloyloacetone is formed during food products preparation and its biological activity has not been fully recognized.
Spices and aromatic herbs have been used since antiquity as preservatives, colorants, and flavor enhancers. Secondary metabolites(SM) are compounds that are not necessary for a cell (organism) to live, but play a role in the interaction of the cell (organism) with its environment. These compounds are often involved in plants protection against biotic or abiotic stresses. Secondary metabolites are mainly responsible for plant defense and have no direct involvement in the growth and development of such plants. Terpenes, alkaloids and phenolics are three main classes of secondary metabolites in plants. Black pepper, cardamom, ginger, turmeric, cinnamon, clove and nutmeg are spices of great commercial importance as it provides flavor and taste to the culinary preparations were it is added. Secondary metabolites of these spices are of great significance in the present era of nutraceuticals as these spices possess antioxidant, anticancerous, numerous other medicinal properties. Detailed information on these spices is very interesting. © Springer International Publishing AG, part of Springer Nature 2018.
Cancer is a major problem of public health and one of the main causes of death around the globe. According to World Health Organization, the prevalence of this disease is rising, however, more rapidly in Africa, Asia, and Central and South America that account for about 70% of cancer deaths in the world. The chemotherapy is one of the ways to treat this disease and the advances in anticancer drugs have improved patient care. Plants have been used to treat different diseases since ancient times. Among the anticancer drugs, about 50% come from natural products as isolated or semisynthetic or related synthetic compounds and plants represent important source of these substances. Taxol, vinca alkaloids, camptothecin, and podophyllotoxins, as well as their semisynthetic or synthetic derivatives, are the most important anticancer drugs obtained from plants. In this chapter, we review the importance of plants as source of drugs and describe these anticancer compounds. The continuing search for antitumor agents from plants is extremely necessary to find the possible ways to have safe and more effective treatment for this health problem.
Self-assembled micelles of octenylsuccinated corn dextrin (OSCD) could be used as a vehicle to disperse curcumin in water, but the resultant solution is inconvenient for storage and transportation. To overcome these shortcomings, curcumin-loaded OSCD micelles were spray-dried with or without maltodextrin (MD). The physico-chemical properties of dried micelles and the stability of their redissolved solutions against thermal, freeze-thaw and acid treatments were investigated. Spray-dried micelles appeared like unaerated balls, and their density, fluidity and curcumin retention increased with the addition of MD. DSC and XRD revealed the amorphous form of curcumin in dried micelles. In terms of curcumin retention, redissolved micelles presented better stability against freeze-thaw and acid treatments than thermal treatment. More importantly, MD highly stabilized the redissolved micelles against freeze-thaw-, acid- and thermal-treatment under 50-70 °C. The present study paves the way for industrial applications of curcumin-loaded OSCD.
Multi-target approach has gained increasing acceptance as useful tool to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β), by attacking both beta-amyloid and tau protein cascades, has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6 and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.
Turmeric (Curcuma longa) is a popular Indian spice that has been used for centuries in herbal medicines for the treatment of a variety of ailments such as rheumatism, diabetic ulcers, anorexia, cough and sinusitis. Curcumin (diferuloylmethane) is the main curcuminoid present in turmeric and responsible for its yellow color. Curcumin has been shown to possess significant anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-mutagenic, anticoagulant and anti-infective effects. This review summarizes and discusses recently published papers on the key biomedical applications of curcumin based materials. The highlighted studies in the review provide evidence of the ability of curcumin to show the significant vitro antioxidant, diabetic complication, antimicrobial, neuroprotective, anti-cancer activities and detection of hypochlorous acid, wound healing, treatment of major depression, healing of paracentesis, and treatment of carcinoma and optical detection of pyrrole properties. Hydrophobic nature of this polyphenolic compound along with its rapid metabolism, physicochemical and biological instability contribute to its poor bioavailability. To redress these problems several approaches have been proposed like encapsulation of curcumin in liposomes and polymeric micelles, inclusion complex formation with cyclodextrin, formation of polymer-curcumin conjugates, etc.
The synthetic compound 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) is a potent analog of curcumin that exhibits enhanced biological activity and bioavailability without increasing toxicity. EF24 exerts antitumor activity by arresting the cell cycle and inducing apoptosis, suppressing many types of cancer cells in vitro. The antiproliferative and antiangiogenic properties of EF24 provide theoretical support for its development and application to liver cancers. We investigated the in vitro and in vivo activities of EF24 on liver cancer to better understand its therapeutic effects and mechanisms. EF24 induced significant apoptosis and G2/M-phase cell cycle arrest in mouse liver cancer cell lines, Hepa1-6 and H22. The expression levels of G2/M cell cycle regulating factors, cyclin B1 and Cdc2, were significantly decreased, pp53, p53, and p21 were significantly increased in EF24-treated cells. In addition, EF24 treatment significantly reduced Bcl-2 concomitant with an increase in Bax, enhanced the release of cytochrome c from the mitochondria into the cytosol, resulting in an upregulation of cleaved-caspase-3, which promoted poly (ADP-ribose) polymerase cleavage. EF24-treated cells also displayed decreases in phosphorylated Akt, phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor. Our in vitro protein expression data were confirmed in vivo using a subcutaneous hepatocellular carcinoma (HCC) tumor model. This mouse HCC model confirmed that total body weight was unchanged following EF24 treatment, although tumor weight was significantly decreased. Using an orthotopic HCC model, EF24 significantly reduced the liver/body weight ratio and relative tumor areas compared to the control group. In situ detection of apoptotic cells and quantification of Ki-67, a biomarker of cell proliferation, all indicated significant tumor suppression with EF24 treatment. These results suggest that EF24 exhibits anti-tumor activity on liver cancer cells via mitochondria-dependent apoptosis and inducing cell cycle arrest coupled with antiangiogenesis. The demonstrated activities of EF24 support its further evaluation as a treatment for human liver cancers.
Many of the health beneficial physiological effects of the spice—turmeric (Curcuma longa), documented in recent years are attributable to the major flavour and colouring compound curcumin. Considerable decrease
in the concentration of bioactive compound curcumin has been observed during the heat processing of turmeric. This study was
aimed at understanding the nature of altered/degraded compounds formed from the bioactive spice compound—curcumin as a result
of heat treatment encountered during domestic cooking. Among several of the degradation compounds of curcumin, three major
ones were characterized as ferulic acid, vanillin and vanillic acid on the basis of their UV absorption, proton NMR spectra
and mass spectral data of LC fractions, as well as by comparison of the three identified compounds with respective standards.
The study confirmed the vulnerability of the diketone bridge in curcumin molecule to heat. In addition, formation of vanillic
acid and vanillin indicated that the molecule is sensitive to heat at the first carbon atom of the alkyl chain which is connecting
the two phenyl moieties.
One swears by whole meal bread, one by sour milk; vegetarianism is the only road to salvation of some, others insist not only on vegetables alone, but on eating those raw. At one time the only thing that matters is calories; at another time they are crazy about vitamins and roughage. The scientific truth may be put quite briefly; eat moderately, have an ordinary mixed diet and don't worry.
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 μm/min) and associated with stoichiometric uptake of O2. Oxidation was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nm; 7.5 μm/min), and the rate was increased ≈10-fold by the addition of 300 μm H2O2. 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 H218O) 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.
1,5-bis(4’-hydroxy-3’-methoxyphenyl)-1,4-pentadiene-3-one is a 1,5-diphenyl-1,4-pentadiene-3-one analogue of curcumin that is produced by modifying the middle site of curcumin leading to 1,4-pentadiene-3-ones to maintain the hydroxy moiety at the aromatic rings that are responsible for its biological activities. Curcumin has been reported to have anti-allergic effects and can inhibit the release of histamine from mast cells. In the present study, we evaluated the anti-allergic effects of 1,5-bis(4’-hydroxy-3’-methoxyphenyl)-1,4-pentadiene-3-one in a mast cell-mediated allergy mode in order to provide information about a newly synthesised-compound for an alternative allergy drug. The study was performed using (1) a rat basophilic leukaemia (RBL-2H3) cell line, which is a tumour analogue of mast cells, with DNP24-BSA, thapsigargin and ionomycin as inducers for secretory markers from mast cells, and (2) an active cutaneous anaphylaxis (ACA) reaction, with ovalbumin as an inductor of mast cell degranulation. Treatment with 1,5-bis(4’-hydroxy-3’-methoxyphenyl)-1,4-pentadiene-3-one strongly inhibited the DNP24-BSA, thapsigargin and ionomycin-mediated release of histamine and β-hexosaminidase from the RBL-2H3 cell line. The results indicated that this compound influenced the activation processes of FcεRI by antigen and intracellular Ca2+ signalling events in mast cells. In type 1 allergy model, this compound also inhibited the active cutaneous anaphylactic reaction on rat dorsal skins generated by ovalbumin. We conclude that the compound 1,5-bis(4’-hydroxy-3’-methoxyphenyl)-1,4-pentadiene-3-one showed anti-allergic activities mediated by mechanisms related to intracellular signalling events in mast cells.
Colorectal carcinoma is one of the major causes of morbidity and mortality in the Western World. Novel therapeutic approaches are needed for colorectal carcinoma. Curcumin, the active component and yellow pigment of turmeric, has been reported to have several anti-cancer activities including anti-proliferation, anti-invasion, and anti-angiogenesis. Clinical trials have suggested that curcumin may serve as a potential preventive or therapeutic agent for colorectal cancer.
We compared the inhibitory effects of curcumin and novel structural analogues, GO-Y030, FLLL-11, and FLLL-12, in three independent human colorectal cancer cell lines, SW480, HT-29, and HCT116. MTT cell viability assay was used to examine the cell viability/proliferation and western blots were used to determine the level of PARP cleavages. Half-Maximal inhibitory concentrations (IC50) were calculated using Sigma Plot 9.0 software.
Curcumin inhibited cell viability in all three of the human colorectal cancer cell lines studied with IC50 values ranging between 10.26 microM and 13.31 microM. GO-Y030, FLLL-11, and FLLL-12 were more potent than curcumin in the inhibition of cell viability in these three human colorectal cancer cell lines with IC50 values ranging between 0.51 microM and 4.48 microM. In addition, FLLL-11 and FLLL-12 exhibit low toxicity to WI-38 normal human lung fibroblasts with an IC-50 value greater than 1,000 microM. GO-Y030, FLLL-11, and FLLL-12 are also more potent than curcumin in the induction of apoptosis, as evidenced by cleaved PARP and cleaved caspase-3 in all three human colorectal cancer cell lines studied.
The results indicate that the three curcumin analogues studied exhibit more potent inhibitory activity than curcumin in human colorectal cancer cells. Thus, they may have translational potential as chemopreventive or therapeutic agents for colorectal carcinoma.
Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.
India is a developing country with one of the most diverse populations and diets in the world. Cancer rates in India are lower than those seen in Western countries, but are rising with increasing migration of rural population to the cities, increase in life expectancy and changes in lifestyles. In India, rates for oral and oesophageal cancers are some of the highest in the world. In contrast, the rates for colorectal, prostate, and lung cancers are one of the lowest. Studies of Indian immigrants in Western societies indicate that rates of cancer and other chronic diseases, such as coronary heart disease and diabetes, increase dramatically after a generation in the adopted country. Change of diet is among the factors that may be responsible for the changing disease rates. Diet in India encompasses diversity unknown to most other countries, with many dietary patterns emanating from cultural and religious teachings that have existed for thousands of years. Very little is known, however, about the role of the Indian diet in causation of cancer or its role, if any, in prevention of cancer, although more attention is being focused on certain aspects of the Indian diet, such as vegetarianism, spices, and food additives. Of particular interest for cancer prevention is the role of turmeric (curcumin), an ingredient in common Indian curry spice. Researchers also have investigated cumin, chilies, kalakhar, Amrita Bindu, and various plant seeds for their apparent cancer preventive properties. Few prospective studies, however, have been conducted to investigate the role of Indian diet and its various components in prevention of cancer. From a public health perspective, there is an increasing need to develop cancer prevention programs responsive to the unique diets and cultural practices of the people of India.
Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a reduction of levels of the oxidative DNA adduct 3-(2-deoxy-β-di-erythro-pentafuranosyl)-pyr[1,2-α]-purin-10(3H)one (M1G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hypothesis that pharmacologically active levels of curcumin can be achieved in the colorectum of humans as measured by effects on levels of M1G and COX-2 protein. Patients with colorectal cancer ingested curcumin capsules (3,600, 1,800, or 450 mg daily) for 7 days. Biopsy samples of normal and malignant colorectal tissue, respectively, were obtained at diagnosis and at 6 to 7 hours after the last dose of curcumin. Blood was taken 1 hour after the last dose of curcumin. Curcumin and its metabolites were detected and quantitated by high-performance liquid chromatography with detection by UV spectrophotometry or mass spectrometry. M1G levels and COX-2 protein expression were measured by immunoslot blot and Western blotting, respectively. The concentrations of curcumin in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7 ± 5.7 and 7.7 ± 1.8 nmol/g, respectively. Curcumin sulfate and curcumin glucuronide were identified in the tissue of these patients. Trace levels of curcumin were found in the peripheral circulation. M1G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). Administration of curcumin (3,600 mg) decreased M1G levels from 4.8 ± 2.9 adducts per 107 nucleotides in malignant colorectal tissue to 2.0 ± 1.8 adducts per 107 nucleotides (P < 0.05 by ANOVA). COX-2 protein levels in malignant colorectal tissue were not affected by curcumin. The results suggest that a daily dose of 3.6 g curcumin achieves pharmacologically efficacious levels in the colorectum with negligible distribution of curcumin outside the gut.
Lipid peroxidation has been implicated in a variety of diseases. 4-Hydroxy-2-nonenal (HNE), a major oxidation by-product, is cytotoxic, mutagenic, and genotoxic, being involved in disease pathogenesis. Naturally occurring pharmacologically active small molecules are very attractive as natural nonsteroidal anti-inflammatory agents. Interest has greatly increased recently in the pharmacotherapeutic potential of curcumin, the yellow pigment found in the rhizomes of the perennial herb Curcuma longa (turmeric). Curcumin is efficacious against colon cancer, cystic fibrosis, and a variety of other disorders. Curcumin's full pharmacological potential is limited owing to its extremely limited water solubility. We report here that the water solubility of curcumin could be increased from 0.6 microg/ml to 7.4 microg/ml (12-fold increase) by the use of heat. Spectrophotometric (400-700 nm) and mass spectrometric profiling of the heat-extracted curcumin displays no significant heat-mediated disintegration of curcumin. Using an enzyme-linked immunosorbent assay that employed HNE modification of solid-phase antigen, we found that the heat-solubilized curcumin inhibited HNE-protein modification by 80%. Thus, inhibition of HNE modification may be a mechanism by which curcumin exerts its effect. We also report a simple assay to detect curcumin spectrophotometrically. Curcumin was solubilized in methanol and serially diluted in methanol to obtain a set of standards that were then read for optical density at 405 nm. Curcumin in the heat-solubilized samples was determined from this standard. Heat-solubilized curcumin should be considered in clinical trials involving curcumin, especially in the face of frustrating results obtained regarding curcumin-mediated correction of cystic fibrosis defects.
Two new natural phenolics were isolated from the rhizomes of Curcuma domestica along with four known curcuminoids. The structures of the former were determined to be 1,5-bis(4-hydroxy-3-methoxyphenyl)-penta-(1E,4E)-1,4-dien-3-one and 1-(4-hydroxy-3-methoxyphenyl)-5-(-4-hydroxyphenyl)-penta-(1E,4E)-1,4-dien-3-one, respectively, by spectral data and syntheses. Anti-oxidant activity of the phenolics was determined by the inhibition of autoxidation of linoleic acid in a water-alcohol system. Anti-inflammatory activity of the isolated compounds was determined on mouse cars by using a tumour promoter, TPA (12-O-tetradecanoylphorbol-13-acetate) as an inducer.
A series of 1,5-diphenyl-1,4-pentadiene-3-ones and cyclic analogues with OH-groups in the para position of the phenyl rings and various meta substituents were prepared and their antioxidant activity compared with that of curcumin. Most of them exhibited potent antioxidative activity, especially when all the meta positions were substituted by methoxy groups.
Curcumin (diferuloylmethane), an active constituent of turmeric, is a well-described phytochemical, which has been used since ancient times for the treatment of various diseases. The dysregulation of cell signaling pathways by the gradual alteration of regulatory proteins is the root cause of cancers. Curcumin modulates regulatory proteins through various molecular mechanisms. Several research studies have provided in-depth analysis of multiple targets through which curcumin induces protective effects against cancers including gastrointestinal, genitourinary, gynecological, hematological, pulmonary, thymic, brain, breast, and bone. The molecular mechanisms of action of curcumin in treating different types of cancers remain under investigation. The multifaceted role of this dietary agent is mediated through its inhibition of several cell signaling pathways at multiple levels. Curcumin has the ability to inhibit carcinogenicity through the modulation of the cell cycle by binding directly and indirectly to molecular targets including transcription factors (NF-kB, STAT3, β-catenin, and AP-1), growth factors (EGF, PDGF, and VEGF), enzymes (COX-2, iNOS, and MMPs), kinases (cyclin D1, CDKs, Akt, PKC, and AMPK), inflammatory cytokines (TNF, MCP, IL-1, and IL-6), upregulation of proapoptotic (Bax, Bad, and Bak) and downregulation of antiapoptotic proteins (Bcl(2) and Bcl-xL). A variety of animal models and human studies have proven that curcumin is safe and well tolerated even at very high doses. This study elaborates the current understanding of the chemopreventive effects of curcumin through its multiple molecular pathways and highlights its therapeutic value in the treatment and prevention of a wide range of cancers. © 2012 BioFactors, 2013.
The kinetics of the pH-dependant degradation of curcumin has been investigated. A plot of the rate constant against pH indicates the pKa values of the acid protons. The graph also indicates the complexity of the curcumin degradation.Es wurde die Kinetik des pH-abhngigen Curcumin-Abbaus untersucht. Eine Darstellung der Geschwindigkeitskonstante gegen die pH-Werte liefert die pKa-Werte des sauren Protonen. Diese Kurve zeigt aber gleichzeitig die Komplexitt des Curcumin-Abbaus an.
The degradation kinetics of curcumin under various pH conditions and the stability of curcumin in physiological matrices were investigated. When curcumin was incubated in 0.1 M phosphate buffer and serum-free medium, pH 7.2 at 37°C, about 90% decomposed within 30 min. A series of pH conditions ranging from 3 to 10 were tested and the result showed that decomposition was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture medium containing 10% fetal calf serum and in human blood; less than 20% of curcumin decomposed within 1 h, and after incubation for 8 h, about 50% of curcumin is still remained. Trans-6-(4′-hydroxy-3′-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major degradation product and vanillin, ferulic acid, feruloyl methane were identified as minor degradation products. The amount of vanillin increased with incubation time.
This paper describes a new method for the preparation of 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one 1 and its derivatives 2-5. This set of synthetic compounds exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines as lung carcinoma NCI-460, melanoma UACC-62, breast MCF-7, colon HT-29, renal 786-O, ovarian OVCAR-03 and ovarian expressing the resistance phenotype for adriamycin NCI-ADR/RES, prostate PC-3, and leukemia K-562. Compounds were also tested against murine tumor cell line B16F10 melanoma and lymphocytic leukemia L1210 as well as to their effect toward normal macrophages. Specific activity against colon cancer cells HT-29 was observed for all tested compounds and suggests further studies with models of colon cancer. Compounds 1, 2, and 4 showed significant cytotoxic activity with IC(50) values 2.3 microM for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate.
Chronic and complex autoimmune diseases, currently treated palliatively with immunosuppressives, require multi-targeted therapy for greater effectiveness. The naturally occurring polyphenol curcumin has emerged as a powerful "nutraceutical" that interacts with multiple targets to regress diseases safely and inexpensively. Up to 8 g/day of curcumin for 18 months was non-toxic to humans. However, 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-solubilized 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-solubilized 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.
Docking analysis of curcumin (C1), demethoxycurcumin (C2) and bisdemethoxycurcumin (C3) with Bcl-2 illustrated that among the three curcuminoids, C2 binds more efficiently into its putative active site. C1, C2 and C3 were purified from turmeric rhizomes to demonstrate the molecular mechanism of their anticancer activity on human glioma U87 cells. Human glioma U87 cells treated with curcuminoids resulted in activation of Bcl-2 mediated G2 checkpoint, which was associated with the induction of G2/M arrest and apoptosis. The binding of C1, C2 and C3 with Bcl-2 protein was confirmed with circular dichroism (CD) spectroscopy. Present work revealed that C2 induced Bcl-2 mediated G2/M arrest and apoptosis most effectively.
Curcumin has a surprisingly wide range of chemo-preventive and chemo-therapeutic activities and is under investigation for the treatment of various human cancers. However, the clinical application of curcumin has been significantly limited by its instability and poor metabolic property. Although a number of synthetic modifications of curcumin have been studied intensively in order to develop a molecule with enhanced bioactivities, few synthetic studies were done for the improvement of pharmacokinetic profiles. In the present study, a series of mono-carbonyl analogues of curcumin were designed and synthesized by deleting the reactive beta-diketone moiety, which was considered to be responsible for the pharmacokinetic limitation of curcumin. The results of the in vitro stability studies and in vivo pharmacokinetic studies indicated that the stability of these mono-carbonyl analogues was greatly enhanced in vitro and their pharmacokinetic profiles were also significantly improved in vivo. Furthermore, the cytotoxic activities of mono-carbonyl analogues were evaluated in seven different tumor cell lines by MTT assay and the structure-activity relation (SAR) was discussed and concluded. The results suggest that the five-carbon linker-containing analogues of curcumin may be favorable for the curcumin-based drug development both pharmacokinetically and pharmacologically.
The relationship between major histocompatibility complex (MHC) antigens and metastasis was investigated on B16 melanoma variants. B16 cell lines express low amounts of murine MHC (H-2) antigens. A high expression can be induced in line B16-A by in vitro treatment with immune interferon (IFN-gamma) or by in vivo transplant in allogeneic mice. The increase of H-2 antigens correlated with an enhancement of lung colonization in young syngeneic mice. The higher metastatic capacity of B16-A cells with induced high levels of H-2 antigens was observed also in adult mice and in young mice pretreated with cyclophosphamide. These results were confirmed investigating the behaviour of a mutant B16 clone (B78H1) which was selectively resistant to the H-2-inducing action of IFN-gamma: lung colonization ability was not increased by IFN pretreatment. The study of variants derived from individual B16-A lung colonies revealed a wide range of H-2 levels. Variants with a low expression had a low colonization ability; one out of two variants with a high H-2 expression also was poorly colonizing. IFN-gamma-mediated H-2 expression appeared to act as an enhancer, rather than a determinant of B16 metastatic capacity.
Turmeric, which is one of the commonly used spices in Indian cooking, was tested for mutagenicity using the Ames test. The alcoholic extract of fresh or dried turmeric, its principal components, and pyrolyzed turmeric powder and curcumin were tested for mutagenicity in Salmonella typhimurium strains with and without metabolic activation. None of these were mutagenic in all the tester strains. Chilies (which are used with turmeric powder) and their principal alkaloid capsaicin were mutagenic in the TA 98 with S9 mixture. We tested curcumin, which is the principal component of turmeric, for its antimutagenic effect. It showed dose-dependent decreases in mutagenicity of chili extract and capsaicin. Also, we compared the antimutagenicity of curcumin with other known antioxidants, including BHA, vitamins E and C, and vegetable oils. These all showed dose-dependent decreases in mutagenicity of chili extract and capsaicin. These studies show that although there are few mutagenic principles in Indian food, there is still quite a large number of antimutagenic principles in the Indian diet that will modulate the activity of environmental mutagens.
The kinetics of the pH-dependent degradation of curcumin has been investigated. A plot of the rate constant against pH indicates the pKa values of the acid protons. The graph also indicates the complexity of the curcumin degradation.
Induction of phase 2 enzymes (e.g., glutathione transferases, NAD(P)H:quinone reductase, glucuronosyltransferases, epoxide hydrolase) is a major strategy for reducing the susceptibility of animal cells to neoplasia and other forms of electrophile toxicity. In a search for new chemoprotective enzyme inducers, a structure-activity analysis was carried out on two types of naturally occurring and synthetic substituted phenylpropenoids: (a) Ar-CH=CH-CO-R, where R is OH, OCH3, CH3, or Ar, including cinnamic, coumaric, ferulic, and sinapic acid derivatives, their ketone analogues, and chalcones; and (b) bis(benzylidene)cycloalkanones, Ar-CH=C(CH2)n(CO)C=CH-Ar, where n = 5, 6, or 7. The potencies of these compounds in inducing NAD(P)H:quinone reductase activity in murine hepatoma cells paralleled their Michael reaction acceptor activity (Talalay, P.; De Long, M. J.; Prochaska, H. J. Proc. Natl. Acad. Sci. U.S.A. 85, 1988, 8261-8265). Unexpectedly, the bis(benzylidene)cycloalkanones also powerfully quenched the lucigenin-derived chemiluminescence evoked by superoxide radicals. Introduction of o-hydroxyl groups on the aromatic rings of these phenylpropenoids dramatically enhanced their potencies not only as inducers for quinone reductase but also as quenchers of superoxide. These potentiating o-hydroxyl groups are hydrogen-bonded, as shown by moderate downfield shift of their proton NMR resonances and their sensitivities to the solvent environment. The finding that the potencies of a series of bis(benzylidene)cycloalkanones in inducing quinone reductase appear to be correlated with their ability to quench superoxide radicals suggests that the regulation of phase 2 enzymes may involve both Michael reaction reactivity and radical quenching mechanisms.
In the course of studies on the antioxidant mechanism of curcumin, its radical reaction was investigated. Curcumin was reacted with radical species, which were generated from the pyrolysis of 2, 2'-azobis(isobutyronitrile) under an oxygen atmosphere, and the reaction products from curcumin were followed by HPLC. The reaction at 70 degrees C gave several products, three of which were structurally identified to be vanillin, ferulic acid, and a dimer of curcumin after their isolation. The dimer was a newly identified compound bearing a dihydrofuran moiety, and its chemical structure was elucidated using spectroscopic analyses, especially 2D NMR techniques. A mechanism for the dimer production is proposed and its relation to curcumin's antioxidant activity discussed. The time course and gel permeation chromatography studies of the reaction were also investigated, and the results indicate that the dimer is a radical-terminated product in the initial stage.
Curcuma spp. extracts, particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day, containing 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies received Curcuma extract daily for up to 4 months. Activity of glutathione S-transferase and levels of a DNA adduct (M(1)G) formed by malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma extract was well tolerated, and dose-limiting toxicity was not observed. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not observed. Leukocytic M(1)G levels were constant within each patient and unaffected by treatment. Radiologically stable disease was demonstrated in five patients for 2-4 months of treatment. The results suggest that (a) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism; and (c) larger clinical trials of Curcuma extract are merited.
From Curcuma longa, two novel compounds, 4' '-(3' "-methoxy-4' "-hydroxyphenyl)-2' '-oxo-3' '-enebutanyl 3-(3'-methoxy-4'hydroxyphenyl)propenoate (calebin-A, 1) and 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (2), and seven known compounds, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin, 3), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (demethoxycurcumin, 4), 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (bisdemethoxycurcumin, 5), 1-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-6-heptene-3,5-dione (6), 1,7-bis(4-hydroxyphenyl)-1-heptene-3,5-dione (7), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (8), and 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (9), were isolated following a bioassay-guided fractionation scheme utilizing an assay to detect protection of PC12 cells from beta-amyloid insult. Compounds 1, 3-5, and 7 were found to more effectively protect PC12 cells from betaA insult (ED(50) = 0.5-10 microg/mL) than Congo red (10) (ED(50) = 37-39 microg/mL).
The activator protein-1 (AP-1) family of transcription factors, including the most common member c-Jun-c-Fos, participates in regulation of expression of numerous genes involved in proliferation, apoptosis, and tumorigenesis in response to a wide array of stimuli including pro-inflammatory cytokines, growth factors, stress, and tumor promoters. A number of plant polyphenols including curcumin, a yellow compound in the spice turmeric, have been shown to inhibit the activation of AP-1. Curcumin is a polyphenolic dienone that is potentially reactive as a Michael acceptor and also is a strong anti-oxidant. Multiple activities reported for curcumin, including inhibition of the stress-induced activation of AP-1, have been suggested to involve the anti-oxidant properties of curcumin. In the present study, a library of analogs of curcumin was screened for activity against the TPA-induced activation of AP-1 using the Panomics AP-1 Reporter 293 stable cell line which is designed for screening potential inhibitors. Numerous analogs were identified that were more active than curcumin, including analogs that were not anti-oxidants and analogs that were not Michael acceptors. Clearly, anti-oxidant activity or reactivity as a Michael acceptor is not an essential feature of active compounds. In addition, a number of analogs were identified that enhanced the TPA-induced activation of AP-1. The results from screening were confirmed using BV-2 microglial cells where curcumin and analogs were shown to inhibit LPS-induced COX-2 expression; analogs identified as more potent than curcumin in the screening assay were also more potent than curcumin in preventing COX-2 expression.