ArticleLiterature Review

Antitumor, anti-invasion, and antimetastatic effects of curcumin

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Abstract

Curcumin was found to be cytotoxic in nature to a wide variety of tumor cell lines of different tissue origin. The action of curcumin is dependent on with the cell type, the concentration of curcumin (IC50: 2-40 microg/mL), and the time of the treatment. The major mechanism by which curcumin induces cytotoxicity is the induction of apoptosis. Curcumin decreased the expression of antiapoptotic members of the Bcl-2 family and elevated the expression of p53, Bax, procaspases 3, 8, and 9. Curcumin prevents the entry of nuclear factor KB (NF-KB) into the nucleus there by decreasing the expression of cell cycle regulatory proteins and survival factors such as Bcl-2 and survivin. Curcumin arrested the cell cycle by preventing the expression of cyclin D1, cdk-1 and cdc-25. Curcumin inhibited the growth of transplantable tumors in different animal models and increased the life span of tumor-harboring animals. Curcumin inhibits metastasis of tumor cells as shown in in vitro as well as in vivo models, and the possible mechanism is the inhibition of matrix metalloproteases. Curcumin was found to suppress the expression of cyclooxygenase-2, vascular endothelial growth factor, and intercellular adhesion molecule- and elevated the expression of antimetastatic proteins, the tissue inhibitor of metalloproteases-2, nonmetastatic gene 23, and Ecadherin. These results indicate that curcumin acts at various stages of tumor cell progression.

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... Several studies have highlighted curcumin's capacity to inhibit the initiation, development, invasion, and metastasis of many tumors through different cell signaling pathways, along with activation of protein kinase pathways [167][168][169][170]. Additional investigations have revealed that curcumin promotes apoptosis by inhibiting anti-apoptotic proteins Bcl-2 and Bcl-xL and activating caspase-3, 8, and 9 in several cancerous cell lines [167][168][169][170][171]. Importantly, curcumin up-regulates the expression of Bax, cytochrome-c, and P53 and down-regulates the expression of Bcl-2 and Bcl-xL in cancer cells [172,173]. Furthermore, some studies have indicated that this compound inhibits the generation of both reactive oxygen and nitrogen (ROS and RNS) species, which accounts for the antioxidant activity of curcumin [169]. Due to the numerous pharmacological effects of curcumin, it should also be emphasized that it inhibits proliferation, invasion, and metastasis of gastric cancerous cells by down-regulation of cyclin D and inhibition of p21activated kinase1 (PAK1) [174]. ...
Article
Helicobacter pylori is a significant human pathogen of the stomach's epithelial lining. This type of carcinogen is associated with gastric cancer, indigestion, peptic ulcers, and upper digestive diseases. Therefore, successful treatment and eradication of this bacterium are required to reduce the prevalence of these diseases, especially in high-risk individuals. Moreover, some concerns exist regarding the extensive use of elimination therapy, such as anti-microbial resistance and rising H. pylori-associated diseases. Since there is still no effective vaccine, finding alternative therapies would appear to be a worthwhile pursuit. In this regard, curcumin exhibits anti-inflammatory, anti-carcinogenic, anti-oxidant properties and is widely used as a natural product-derived medicine or nutraceutical. Furthermore, curcumin has been reported to have anti-bacterial activity. Therefore, curcumin might be an effective herbal-based medicine for preventing, managing, or treating H. pylori infection. This review discusses the anti-inflammatory, anti-cancer, and anti-bacterial properties of curcumin as it pertains to gastric cancer and H. pylori-associated diseases.
... A good correlation was observed between the total polyphenol contents and proliferation activity in seaweed extracts (R 2 = 0.686) (Figure 3). The anticancer activity of polyphenols could be induced via Natural Science multiple anticancer pathways such as interaction with key enzymes in cellular signaling pathways, cell cycle, apoptosis and metastasis [42,43]. ...
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Seaweeds are considered as one of the largest biomass producers in marine environment that is rich in bioactive metabolites and a source of natural ingredients for functional foods. The potential antioxidant activity and the potential inhibition of Caco2 cell proliferation, of crude extracts of: Chlorophyta (Ulva lactuca , and Codium tomentosum), Phaeophyta (Cystoseira crinita , Cystoseira stricta , and Sargassum vulgare) , and Rhodophyta (Gelidium latifolium, Hypnea musciformis , and Jania rubens ) were collected from western Libyan coast and evaluated in vitro . The antioxidant activity was determined by reducing power and DPPH assays while cell proliferation, morphological changes and the cell cycle arrest were assessed by MTT, inverted light microscope and flow cytometry methods respectively. The polyphenols and flavonoids rich extracts showed remarkable reducing power and antiradical properties. After exposure of Caco2 cells to various concentrations of extracts (50, 100, 150 and 200 μg/mL) especially from brown algae for 72 h, cell proliferation was reduced significantly. The antiproliferative effect of algae extracts was correlated with their polyphenol and flavonoid contents. Cell cycle analysis further showed that cells were arrested in G phases along with an increment in sub-diploidal cell population (sub-G) after extract application. These results imply that seaweeds which are rich in bioactive compounds may be used in anticancer drug research programs. However, further investigations are essential to reveal the molecular mechanisms of the anticancer activities of these algae.
... Metastasis is the primary cause of high mortality rate seen in cancer patients [68] which justifies the requirement of drugs with migrastatic potential. Previous reports have established the migrastatic property of curcumin [69] in cancer cells. Metastatic cell types undergo EMT (Epithelial to mesenchymal transition) during metastasis [70]. ...
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Background: Curcumin is known for its multitude of medicinal properties, including anti-cancer and migrastatic activity. Efforts to overcome poor bioavailability, stability, and side effects associated with the higher dose of curcumin has led to the development of newer derivatives of curcumin. Thus, the focus of this study is to screen novel curcumin derivatives, namely ST03 and ST08, which have not been reported before, for their cytotoxicity and migrastatic property on cancer cells. Methods: Anti-cancer activity of ST03 and ST08 was carried out using standard cytotoxicity assays viz., LDH, MTT, and Trypan blue on both solid and liquid cancer types. Flow cytometric assays and western blotting was used to investigate the cell death mechanisms. Transwell migration assay was carried out to check for migrastatic properties of the compounds. Results: Both the compounds, ST03 and ST08, showed ~ 100 fold higher potency on liquid and solid tumour cell lines compared to its parent compound curcumin. They induced cytotoxicity by activating the intrinsic pathway of apoptosis in the breast (MDA-MB-231) and ovarian cancer cell lines (PA-1) bearing metastatic and stem cell properties, respectively. Moreover, ST08 also showed inhibition on breast cancer cell migration by inhibiting MMP1 (matrix metalloproteinase 1). Conclusion: Both ST03 and ST08 exhibit anti-cancer activity at nanomolar concentration. They induce cell death by activating the intrinsic pathway of apoptosis. Also, they inhibit migration of the cancer cells by inhibiting MMP1 in breast cancer cells.
... Many studies reported the pharmacological efficiency of curcumin in the treatment of gastric cancer. Curcumin exerted its antitumor action by means of inhibition of antiapoptotic proteins of the Bcl-2 family and elevated the expression of p53, Bax, procaspases 3, 8, and 9 [69]. ...
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Curcumin, a polyphenol extracted from Curcuma longa in 1815, has gained attention from scientists worldwide for its biological activities (e.g., antioxidant, anti-inflammatory, antimicrobial, antiviral), among which its anticancer potential has been the most described and still remains under investigation. The present review focuses on the cell signaling pathways involved in cancer development and proliferation, and which are targeted by curcumin. Curcumin has been reported to modulate growth factors, enzymes, transcription factors, kinase, inflammatory cytokines, and proapoptotic (by upregulation) and antiapoptotic (by downregulation) proteins. This polyphenol compound, alone or combined with other agents, could represent an effective drug for cancer therapy.
... Curcumin, has been shown to be effective against different cancers [12][13][14] in both in vitro and in vivo assays through a variety of mechanisms [15,16]. In addition, human clinical trials did not demonstrate any toxicity for curcumin at doses up to 10 g/day [17]. ...
... Another biologically active polyphenolic compound is curcumin, which is found in turmeric, a spice derived from the rhizomes of the plant Curcuma longa Linn. Many preclinical studies show that curcumin modulates numerous molecular targets and exerts antioxidant, anti-inflammatory, anticancer, and neuroprotective activities [125]. Furthermore, curcumin is important to prevent and treat Type 2 diabetes mellitus disease [126]. ...
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Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength. In older people, malnutrition and physical inactivity are often associated with sarcopenia, and, therefore, dietary interventions and exercise must be considered to prevent, delay, or treat it. Among the pathophysiological mechanisms leading to sarcopenia, a key role is played by an increase in reactive oxygen and nitrogen species (ROS/RNS) levels and a decrease in enzymatic antioxidant protection leading to oxidative stress. Many studies have evaluated, in addition to the effects of exercise, the effects of antioxidant dietary supplements in limiting age-related muscle mass and performance, but the data which have been reported are conflicting. In skeletal muscle, ROS/RNS have a dual function: at low levels they increase muscle force and adaptation to exercise, while at high levels they lead to a decline of muscle performance. Controversial results obtained with antioxidant supplementation in older persons could in part reflect the lack of univocal effects of ROS on muscle mass and function. The purpose of this review is to examine the molecular mechanisms underlying the dual effects of ROS in skeletal muscle function and the analysis of literature data on dietary antioxidant supplementation associated with exercise in normal and sarcopenic subjects.
... Another classis combination is DOX and CUR. CUR was believed to inhibit the tumor growth by causing cell cycle arrest [133,134], inducing an apoptotic signal [135,136], reversing multidrug resistance [137] and inhibiting the activation of NF-κB [138,139]. The exact molecular mechanisms of curcumin-induced apoptosis in cancer cells varied and depended on the cell type and dose used [140]. ...
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Multiple factors are involved in the development of cancers and their effects on survival rate. Many are related to chemo-resistance of tumor cells. Thus, treatment with a single therapeutic agent is often inadequate for successful cancer therapy. Ideally, combination therapy inhibits tumor growth through multiple pathways by enhancing the performance of each individual therapy, often resulting in a synergistic effect. Polymeric nanoparticles prepared from block co-polymers have been a popular platform for co-delivery of combinations of drugs associated with the multiple functional compartments within such nanoparticles. Various polymeric nanoparticles have been applied to achieve enhanced therapeutic efficacy in cancer therapy. However, reported drug ratios used in such systems often vary widely. Thus, the same combination of drugs may result in very different therapeutic outcomes. In this review, we investigated polymeric co-delivery systems used in cancer treatment and the drug combinations used in these systems for synergistic anti-cancer effect. Development of polymeric co-delivery systems for a maximized therapeutic effect requires a deeper understanding of the optimal ratio among therapeutic agents and the natural heterogenicity of tumors.
... In cell adhesion assays, curcumin-treated cells showed a dose-dependent reduction in their binding to four extracellular matrix proteins (binding to proteins is associated with the spreading of the cancer). Another study found that curcumin effectively suppressed COX-2, vascular endothelial growth factor and intercellular adhesion molecules, while enhancing the expression of antimetastatic proteins, tissue inhibitor metalloproteases-2, non-metastatic gene 23 and E-cadherin, a transmembrane protein that plays an important role in cell adhesion (Kuttan et al 2007). Curcumin-treated cells showed a marked reduction in the expression of integrin receptors (integrins functionally connect the cell interior with the extracellular matrix, another process necessary for metastases). ...
Chapter
Among the plants known for their medicinal values, the plants of the Curcuma genus, which encompass 70 known species, have been traditionally used as a spices, food preservatives, and coloring materials, and are highly significant for their therapeutic potential (Krup et al., 2013). Curcuma longa L., or turmeric, is an everlasting herb and member of the Zingiberaceae (ginger) family which is cultured widely in South East Asia, mostly in India and China (Labban, 2014; Mehrotra et al., 2013). The height of the C. longa tree is approximately 91.44 cm and their leaves appear like lance structures with yellow flower prickles that ripen in its fleshy rhizome or in its underground stem. The source of turmeric medicinal powder is the orange pulp enclosed inside the rhizome (Kocaadam and Şanlier, 2015; Ulbricht et al., 2011). Dried C. longa is the main source of turmeric. The vigorous component of turmeric and the one responsible for its yellow color is known by different names in different countries, for example, it is named curcumin (Fig. 3.43.1) in Arab countries, in India it is called saffron or Haridra (Sanskrit, Ayurvedic), it is known as Jianghuang (yellow ginger) in China, and Kyoo or Ukon in Japan (Goel et al., 2008).
... Curcumin exhibits various biological properties such as anticancer and anti-inflammatory. Therefore, it can be used in the treatment of several disorders, such as tumors and pro-inflammatory chronic diseases [71][72][73]. Because of the insufficient aqueous solubility and bioavailability of curcumin, it is not widely used in the clinical field for treatment of cancer and other diseases [74]. ...
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Terpineols are monocyclic monoterpene tertiary alcohols which are naturally present in plant species. There are five common isomers of terpineols, alpha-, beta-, gamma-, delta- and terpinen-4-ol, of which α-terpineol and its isomer terpinen-4-ol are the most common terpineols found in nature. α-Terpineol plays an important role in the industrial field. It has a pleasant odor similar to lilacs and it is a common ingredient in perfumes, cosmetics, and aromatic scents. In addition, α-terpineol attracts a great interest as it has a wide range of biological applications as an antioxidant, anticancer, anticonvulsant, antiulcer, antihypertensive, anti-nociceptive compound. It is also used to enhance skin penetration, and also has insecticidal properties. This study reviews the relevance of α-terpineol based on scientific findings on Google Scholar, Pubmed, Web of Science, Scopus and Chemical Abstracts. Collectively, the use of α-terpineol in medicine and in the pharmaceutical industry plays an important role in therapeutic applications. This review will, therefore, support future research in the utilization of α-terpineol.
... Recently, an entire book was dedicated to the beneficial actions of curcumin (The Molecular Targets and Therapeutic uses of Curcumin in Health and Disease, 2007). Several investigators focused on the molecular targets of curcumin, including NRF2, on curcumin action, and its uses as a neuroprotective agent against toxicants inducing oxidative stress but also as an antitumor agent [91][92][93]. The molecular action is non-specific with multiple systems and pathways being affected, including the involvement of NRF2 [94]. ...
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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.
... This compound has been investigated in clinical trials for its potential therapeutic properties, including anticancer activity (Surh & Chun 2007, Pari et al. 2008, Strimpakos & Sharma 2008. Artumerone acts through various mechanisms, including the induction of apoptosis, inhibition of angiogenesis, and modulation Lovaglio of tumor suppressor genes (Bhandarkar & Arbiser 2007, Kuttan et al. 2007 ...
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How well modified wood products perform may be influenced by their chemical compositions. Wood extractives are nonstructural constituents, many with specific biological properties, which affect the color, fragrance, hygroscopicity, durability, and acoustic properties and the drying and adhesion processes of wood. However, incomplete information is available on the extraction techniques and potential use of extractives as value-added chemical products. The main goal of this research was to explore the effects of thermo-vacuum treatment of Deodar cedar (Cedrus deodara Roxb.) and Italian alder (Alnus cordata Desf.) woods on the content and composition of extractives. Solvents with different polarities were used, including water, hexane, dichloromethane, meth-anol, and a benzene/ethanol mixture. Component groups in extracts were determined by gas chromatography in combination with mass spectrometry. Regardless of the treatment and solvent, the most representative extracts to be obtained from alder were acids/esters, whereas hydrocarbons were most frequently obtained from cedar. Our results revealed an interesting differential species-specific effect of solvents on the composition of extracts. Aside from benzene/ethanol, greater amounts of extracts were obtained from treated than from untreated alder, whereas the opposite was true for cedar, aside from methanol.
... Several reports have demonstrated that curcumin prevents cancer progression through its anti-inflammatory, antioxidant, anti-proliferative, and pro-apoptotic activities. Although the mechanism of action for this dietary agent has yet to be fully understood, it is believed that curcumin directly interacts with several proteins, including inflammatory molecules, cell survival proteins, histone acetyltransferases(HATs), histone deacetylases (HDAC), protein kinases and reductases, glyoxalase I (GLOI), proteasome, sarcoplasmicreticulum Ca 2+ ATPase (SERCA), human immune deficiency virus type 1 (HIV1) integrase and protease, DNAmethyltransferases 1 (DNMT1), FtsZ protofilaments, carrier proteins, DNA, RNA, and metal ions [21][22][23][24][25]. Curcumin also affects several transcription factors and co-factors, including nuclear factor-kappa-B (NF-κB) [26][27][28][29], activator protein 1 (AP-1) [30], β-catentin [31,32], signal transducer and activator of transcription3 (STAT3) protein [33,34], and peroxisome proliferator-activated receptor γ (PPARy) [35,36]. The effects of curcumin are mediated, at least inpart, through intrinsic and extrinsic apoptosis, p53 [37,38], NF-κB and NF-κB-regulated gene expression of B cell lymphoma 2 (Bcl2) [39][40][41][42], cyclin D1 [36], cyclooxygenase-2 (COX-2) [43], matrix metalloproteinase-9 (MMP-9) [44,45], Akt [46], mitogen activate protein kinase (MAPK) [47,48], NF-E2-relatedfactor 2 (Nrf2) [49], and cell-cell adhesion. ...
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Background Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcumin in regulating cellular bioenergetic processes remains largely unknown. Methods Western blotting and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. RTCA, CCK-8 assay, nude mice xenograft assay, and in vivo bioluminescence imaging were used to visualize the effects of curcmin on gastric cancer cell growth in vitro and in vivo. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. ResultsCurcumin significantly inhibited gastric tumor cell growth, proliferation and colony formation. We further investigated the role of curcumin in regulating cellular redox homeostasis and demonstrated that curcumin initiated severe cellular apoptosis via disrupting mitochondrial homeostasis, thereby enhancing cellular oxidative stress in gastric cancer cells. Furthermore, curcumin dramatically decreased mtDNA content and DNA polymerase ? (POLG) which contributed to reduced mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion via ROS generation, and POLG knockdown also reduced oxidative phosphorylation (OXPHOS) activity and cellular glycolytic rate which was partially rescued by ROS scavenger NAC, indiating POLG plays an important role in the treatment of gastric cancer. Data in the nude mice model verified that curcumin treatment significantly attenuated tumor growth in vivo. Finally, POLG was up-regulated in human gastric cancer tissues and primary gastric cancer cell growth was notably suppressed due to POLG deficiency. Conclusions Together, our data suggest a novel mechanism by which curcumin inhibited gastric tumor growth through excessive ROS generation, resulting in depletion of POLG and mtDNA, and the subsequent disruption of cellular bioenergetics.
... Curcuminoids and curcumin exhibit multiple biological activities including anti-inflammatory, anticancer, antioxidant, wound healing and antimicrobial effects ( Maheshwari et al., 2006). Curcumin is used to treat various disorders like tumors ( Kuttan et al., 2007) and proinflammatory chronic diseases (Menon and Sudheer, 2007). It has also been found to exert beneficial effects on experimental models of Alzheimer's disease ( Hamaguchi et al., 2010). ...
Chapter
Nanoemulsions have considerable potential for encapsulating, protecting, and delivering lipophilic and hydrophilic bioactive components via different routes, most commonly; transdermal and oral. The bioactive components may be pharmaceuticals (drugs) and nutraceuticals (phytonutrients with specific health benefits). Nanoemulsions can be fabricated from generally recognized as safe ingredients, using usually simple processing operations. Some of the potential advantages of nanoemulsions include higher bioaccessibility, physical stability, and optical clarity, in addition to small particle size, controlled release of actives with prolonged duration of action. Many phytonutrients have shown promise as curative agents. Various types of nanoparticles, such as nano-/microemulsions, have proved suitable for the delivery of active forms of phytonutrients. Examples include curcumin microemulsions that improved its delivery via local and transdermal routes. Also, wheat bran oil nanoemulsions showed good stability over time together with antioxidant activity making it suitable for use in food applications. Liquorice transdermal microemulsions (TD ME) possessed potent antioxidant capacity and good stability. Also, the boswellia TD MEs provided excellent prolonged anti-inflammatory potential with no local irritation. Fennel essential oil transdermal nanoemulsions proved to have a potent antidiabetic effect with a prolonged action. Other contributions comprise cumin essential oil for transdermal antioxidant activity.
... However, an extensive research has been developed to determine anticancer effect of curcumin which is obtained from the rhizome of Curcuma longa. Cur inhibit the growth of transplantable tumors in different animal models and increases life span of tumor Curcumin thus exhibits a great promise as a therapeutic agent and is currently in human clinical trials fo multiple myeloma, pancreatic cancer, colon cancer and myelodisplastic syndromes [7,8]. Apart from curcumin plant derived This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. ...
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p>During past few decades cancer has remained as the largest cause of mortality worldwide and number of patients suffering from cancer has been increasing at a fast rate. Hence medical research during the last few decades has been concentrating on identification and characterization of new synthetic pharmacological compounds to overcome this enormous problem. Leaf extracts of coniferous plant Cryptomeria japonica being known for their strong antibacterial and antifungal functions were selected to determine their antitumor/anticancer potentialities. Methanolic extract of leaves were tested to determine its antitumor action in standard murine model of Ehrlich Ascites Carcinoma (EAC). Graded doses of the extract were given intraperitoneally to batches of mice, who received EAC challenge after 3hr. Treatment with same amounts of extract was continued for 9 consecutive days. Protective capacity of the leaf extract was evaluated in animals. Statistically significant protection was observed with respect to different parameters including tumor volume , tumor cell count , viable tumor cell count, non- viable tumor cell count , mean survival time and increase in life span. Simultaneously hematological parameters were restored in treated mice vis-à-vis untreated control animals. Furthermore, the extract revealed distinct cytotoxic property, which may be the relevant reason of its anticancer/antitumor function. This study shows efficacy of methanolic extract of leaves of Cryptomeria japonica as a probable antitumor/anticancer agent. Phytochemical analysis of the extract showed presence of flavonoids, which are known to possess significant anticancer activity. Thus there is a definite possibility of developing novel anticancer drugs from such plant products
... A good correlation was observed between the total polyphenol contents and proliferation activity in seaweed extracts (R 2 = 0.686) (Figure 3). The anticancer activity of polyphenols could be induced via Natural Science multiple anticancer pathways such as interaction with key enzymes in cellular signaling pathways, cell cycle, apoptosis and metastasis [42,43]. ...
Article
Seaweeds are considered as one of the largest biomass producers in marine environment that is rich in bioactive metabolites and a source of natural ingredients for functional foods. The potential antioxidant activity and the potential inhibition of Caco2 cell proliferation, of crude extracts of: Chlorophyta (Ulva lactuca, and Codium tomentosum), Phaeophyta (Cystoseira crinita, Cystoseira stricta, and Sargassum vulgare), and Rhodophyta (Gelidium latifolium, Hypnea musciformis, and Jania rubens) collected from western Libyan coast were evaluated in vitro. The antioxidant activity was determined by reducing power and DPPH assays while cell proliferation, morphological changes and the cell cycle arrest were assessed by MTT, inverted light microscope and flow cytometry methods respectively. The polyphenols and flavonoids rich extracts showed remarkable reducing power and antiradical properties. After exposure of Caco2 cells to; various concentrations of extracts (50, 100,150 and 200 µg/mL) especially from brown algae for 72 h, significantly reduced cell proliferation. The antiproliferative effect of algae extracts was correlated with their polyphenol and flavonoid contents. Cell cycle analysis further showed that cells were arrested in G phases along with an increment in sub-diploidal cell population (sub-G) after extract application. These results imply that seaweeds which are rich in bioactive compounds may be in anticancer drug research programs. However, further investigations are essential to reveal the molecular mechanisms of the anticancer activities of these algae.
... Ectopic overexpression of cortactin resulted in increased endothelial and fibroblast cell migration [8,9]. Since curcumin has been described to reduce the invasion of several types of cancer partly via inhibition of matrix metalloproteases [46][47][48][49], to avoid the confounding effects of curcumin on proteolitic enzymes, we tested if overexpression of cortactin and/or curcumin can modify HCT116, SW480, and HT29 colon cancer cell migration through uncoated semi-permeable membranes, as described in Materials and Methods. As shown in Fig. 6A, infection of all three colon cancer cell lines with adenovirus encoding CTTN (Ad-CTTN) led to a significant increase in CTTN mRNA expression, which was especially prominent in HCT29 cells. ...
Article
Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr 421) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr 421-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr 421-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr 421-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr 421-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr 421-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr 421-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr 421-CTTN expression.
... Inhibition of upstream kinases JAK1/2 and Src, and upregulation and/or activation of SHP1 or other protein tyrosine phosphatases appear to be a common feature of these compounds. Curcumin, a naturally derived phytochemical from plants such as turmeric (Curcuma longa), has been extensively investigated for its anti-tumor effects [278]. Curcumin was shown to block STAT3 and/or STAT5 phosphorylation in leukemia, lymphoma, and myeloma cells ( Table 2) [279][280][281][282][283]. ...
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Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.
... More than 40 clinical trials using curcumin were developed for the treatment of inflammatory diseases and various human cancers (Huang et al., 1988;Aoki et al., 2007;Kuttan et al., 2007). However, phase I/II clinical trials have shown that curcumin exhibits poor bioavailability in humans (Anand et al., 2007). ...
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AXL is an important drug target for cancers. Two-dimensional quantitative structure-activity relationship (2D-QSAR) tests were performed to elucidate a relationship between molecular structures and the activity of a series of 400 curcumin derivatives subjected to AXL kinase by ATP competition in the catalytic site. The partial least square regression method implanted in molecular operating environment software was applied to develop QSAR models, which were further validated for statistical significance by internal and external validation. The best model has proven to be statistically robust with a good predictive correlation of R 2 = 0.996 and a significant cross-validation correlation coefficient of q 2 = 0.707. Docking analysis reveled that three curcumin derivatives have the best affinity for AXL and formed a hydrogen bond with the important amino acid residues in the binding pocket. As treated in this article, the docking studies and 2D-QSAR approach will pave the way for the development of new drugs while highlighting curcumin and its derivatives.
... In SiHa cells and HCT116 cells, curcumin is found to upregulate p53 and Beclin-1 and induce reactive oxygen species (ROS) in activation of autophagy (Lee et al., 2011;Wang T. et al., 2020). Besides that, curcumin exerts its antitumor action inhibiting Bcl-2 and elevating the expression of Bax, p53, procaspases 3, 8, and 9 (Kuttan et al., 2007). YAP and P62 are observed to be reduced and LC3-Ⅱis enhanced with the treatment of curcumin in HCT116 and SW620. ...
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Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.
... As a traditional Chinese herbal medicine, Curcuma longa has been applied for a long time in many traditional medicine systems to treat several cardiovascular diseases because of its capacity to "invigorate blood" [14]. Curcumin is the chief component of Curcuma longa and has various beneficial effects, including anti-inflammatory [15], antitumor [16], antioxidative [17], wound healing [18], and anti-infective effects [19]. Currently, curcumin is regarded as a health care product and is contained in the British Pharmacopoeia, United States Pharmacopeia, and European Pharmacopoeia [20]. ...
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Excessive free fatty acid- (FFA-) induced endothelial lipotoxicity is involved in the pathogenesis of atherosclerosis. Endoplasmic reticulum (ER) stress is mechanistically related to endothelial lipotoxicity. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major oxidatively modified low-density lipoprotein (OxLDL) receptor in endothelial cells and is highly abundant in atherosclerotic lesions. Curcumin reduces the LOX-1 expression; however, the mechanism underlying this effect remains unknown. In the current study, we explored whether curcumin ameliorates palmitic acid- (PA-) induced endothelial lipotoxicity and LOX-1 upregulation by reducing ER stress in human umbilical vein endothelial cells (HUVECs). We built endothelial lipotoxicity in vitro and found that LOX-1 was upregulated after PA stimulation, during which ER stress played an important role. Next, we observed that curcumin substantially alleviated PA-induced lipotoxicity by restoring cell viability, increasing angiogenesis, and decreasing lipid deposition. Furthermore, LOX-1 upregulation in HUVECs was blocked by curcumin, possibly via ER stress suppression. Overall, our findings demonstrated that curcumin alleviates endothelial lipotoxicity and LOX-1 upregulation, and ER stress inhibition may play a critical role in this effect.
... As a polyphenol, curcumin could activate kelch-like ECH-associated protein 1-Nrf2-EpRE pathway and display oxidant activity [21,26]. Furthermore, cumulative studies have suggested that curcumin was helpful in treating skin diseases, such as psoriasis, scleroderma, and skin cancer [27][28][29][30]. Curcumin suppressed UV-induced skin carcinogenesis by alleviating UVB radiationinduced acute inflammation and photoaging [5]. ...
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Curcumin suppressed ultraviolet (UV) induced skin carcinogenesis and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. However, whether curcumin protects skin injury caused by UV is still unknown. A vitro model was established and curcumin effects on Hacat cells were detected. Nrf2 was knocked down in Hacat cells to verify the Nrf2 role in the protective effect of curcumin. Results indicated that ultraviolet A (UVA) (or ultraviolet B (UVB)) irradiation would lead to decreased cell proliferation, increased cell apoptosis, decreased catalase, heme oxygenase 1, and superoxide dismutase expression, and increased levels of protein carbonylation and malondialdehyde (p < 0.05). These adverse events could be reversed by adding 5-μM curcumin. Meanwhile, we found that the application of curcumin effectively induced Nrf2 nuclear accumulation in Hacat cells. While in the Nrf2 knockdown cells, the protective effects of curcumin against UVA (or UVB) were attenuated. Conclusively, curcumin protects Hacat cells against UV exposure-induced photo-damage by regulating Nrf2 expression.
... The anticancer action of curcumin is mainly associated with its antiproliferative and proapoptotic effects, which have been mostly shown in vitro studies in human colon cancer cells (Basile et al., 2013), human papillary thyroid carcinoma cells (BCPAP) , K562 cell line of CML (Larasati et al., 2018) and in B-precursor lymphoblastic leukemia (ALL) (B-Pre-ALL) cell lines (Kuttikrishnan et al., 2019). In vivo, curcumin has been shown to prevent cancer cells spread (Kuttan, Kumar, Guruvayoorappan, & Kuttan, 2007) and inhibit angiogenesis (Bhandarkar & Arbiser, 2007). ...
Article
Recently, many studies have been conducted trying to explain the molecular mechanism of curcumin action in various pathological states of the cell and the organism. Curcumin is considered to play a role in the regulation of T‐lymphocytes function in the lymphoid tissue of the large intestine, apoptosis of the human papilloma and the activity of the 26S proteasome, and p53 level. Research works have shown that curcumin in tumor can regulate reactive oxygen species (ROS) and cytosolic calcium ion level as well as affect other signaling molecules [nuclear factor kappa B (NF‐KB), cytokines] triggering endoplasmic reticulum and mitochondrial stress, and thus contributing to death of cancer cells. Curcumin can also arrest of the cell cycle in the G2/M phase leading to apoptosis and/or reduction in cancer cells proliferation. Moreover, curcumin is capable of crossing the blood–brain barrier, and thus it may protect the neurons from oxidative stress and inflammation. Finally, curcumin may play a role in cardiological protection and it is possible to use it in the protection of liver and spleen against oxidative and inflammatory injury. Among signaling pathways regulated by curcumin, the most important seem to be those related with regulation of oxidative stress and inhibition of NF‐кB activity. The curcumin modulates various signaling pathways, therefore protecting organism against different diseases.
... The scientific literature offers various examples in other types of cancer (lung, colorectal, liver, and pancreas), but the mechanisms are always related to proliferative reduction, the onset of apoptosis, and cell cycle blockage [165]. Curcumin has been tested on animal models, and the optimal dose to reduce cancer was found to be 300 mg/kg [166]. In humans, early preclinical studies were conducted to evaluate the tolerated dose, but further studies should nevertheless be conducted [167]. ...
Article
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Cancer is one of the leading causes of death globally, associated with multifactorial pathophysiological components. In particular, genetic mutations, infection or inflammation, unhealthy eating habits, exposition to radiation, work stress, and/or intake of toxins have been found to contribute to the development and progression of cancer disease states. Early detection of cancer and proper treatment have been found to enhance the chances of survival and healing, but the side effects of anticancer drugs still produce detrimental responses that counteract the benefits of treatment in terms of hospitalization and survival. Recently, several natural bioactive compounds were found to possess anticancer properties, capable of killing transformed or cancerous cells without being toxic to their normal counterparts. This effect occurs when natural products are associated with conventional treatments, thereby suggesting that nutraceutical supplementation may contribute to successful anticancer therapy. This review aims to discuss the current literature on four natural bioactive extracts mostly characterized by a specific polyphenolic profile. In particular, several activities have been reported to contribute to nutraceutical support in anticancer treatment: (1) inhibition of cell proliferation, (2) antioxidant activity, and (3) anti-inflammatory activity. On the other hand, owing to their attenuation of the toxic effect of current anticancer therapies, natural antioxidants may contribute to improving the compliance of patients undergoing anticancer treatment. Thus, nutraceutical supplementation, along with current anticancer drug treatment, may be considered for better responses and compliance in patients with cancer. It should be noted, however, that when data from studies with bioactive plant preparations are discussed, it is appropriate to ensure that experiments have been conducted in accordance with accepted pharmacological research practices so as not to disclose information that is only partially correct.
... This compound has been investigated in clinical trials for its potential therapeutic properties, including anticancer activity (Strimpakos and Sharma 2008). Ar-Tumerone acts through various mechanisms, including the induction of apoptosis, inhibition of angiogenesis, and modulation of tumor suppressor genes (Kuttan et al. 2007). ...
Chapter
Mass spectrometry is the election method used to identify the structure of volatile organic compounds in natural matrices. The use of this methodology in the determination of VOCs in virgin olive
... Curcumin inhibits anti-apoptotic Bcl-2 proteins family in intestinal epithelial cells and stimulates the expression of p53, Bax, procaspases 3, 8, and 9 and the pro-apoptotic Bax protein [89]. Curcumin binds vitamin D receptor present in intestinal epithelial cells involved in the promotion of colon cancer chemopreventing process [90]. ...
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The Mediterranean diet is a central element of a healthy lifestyle, where polyphenols play a key role due to their anti-oxidant properties, and for some of them, as nutripharmacological compounds capable of preventing a number of diseases, including cancer. Due to the high prevalence of intestinal cancer (ranking second in causing morbidity and mortality), this review is focused on the beneficial effects of selected dietary phytophenols, largely present in Mediterranean cooking: apigenin, curcumin, epigallocatechin gallate, quercetin-rutine, and resveratrol. The role of the Mediterranean diet in the prevention of colorectal cancer and future perspectives are discussed in terms of food polyphenol content, the effectiveness, the plasma level, and the importance of other factors, such as the polyphenol metabolites and the influence of the microbiome. Perspectives are discussed in terms of microbiome-dependency of the brain-second brain axis. The emergence of polyphenol formulations may strengthen the efficiency of the Mediterranean diet in the prevention of cancer.
... [34][35][36] Prior types of research have proved that turmeric can interfere at varied phases of the cell cycle through suppression of DNA synthesis, downregulation of cyclin D1, provocation of p53 and cyclin-dependent kinase inhibitors, as well as retardation of NF-κB. [37][38][39] Prakasunand C et al., observed in 54 cases of peptic ulcer who were given 2 capsules of turmeric (300 mg each) 5 times daily for 4 weeks & reached a healing rate of 48%. 40 Similarly in the present study, we observed reduction in ulceration of oral mucosa in 40% of OSMF patients (groups A & B). ...
... MMPs are important substances that degrade the ECM. MMP9 can degrade the major components of the ECM, the basement membrane collagen types IV and V. Therefore, its activity is closely associated with the angiogenesis, invasion, and metastasis of tumor cells [53,54] . Cur can inhibit NF-κB, as well as the activity of MMP-2 and MMP9, thereby exerting its effect against tumor metastasis and invasion [55] . ...
Article
Background: Liver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality. The pathogenesis of liver cancer is closely associated with inflammation and immune response in the tumor microenvironment. New therapeutic agents for liver cancer, which can control inflammation and restore cellular immunity, are required. Curcumin (Cur) is a natural anti-inflammatory drug, and total ginsenosides (TG) are a commonly used immunoregulatory drug. Of note, both Cur and TG have been shown to exert anti-liver cancer effects. Aim: To determine the synergistic immunomodulatory and anti-inflammatory effects of Cur combined with TG in a mouse model of subcutaneous liver cancer. Methods: A subcutaneous liver cancer model was established in BALB/c mice by a subcutaneous injection of hepatoma cell line. Animals were treated with Cur (200 mg/kg per day), TG (104 mg/kg per day or 520 mg/kg per day), the combination of Cur (200 mg/kg per day) and TG (104 mg/kg per day or 520 mg/kg per day), or 5-fluorouracil combined with cisplatin as a positive control for 21 d. Tumor volume was measured and the protein expression of programmed cell death 1 and programmed cell death 1 ligand 1 (PD-L1), inflammatory indicators Toll like receptor 4 (TLR4) and nuclear factor-κB (NF-κB), and vascular growth-related factors nitric oxide synthases (iNOS) and matrix metalloproteinase 9 were analyzed by Western blot analysis. CD4+CD25+Foxp3+ regulatory T cells (Tregs) were counted by flow cytometry. Results: The combination therapy of Cur and TG significantly inhibited the growth of liver cancer, as compared to vehicle-treated animals, and TG showed dose dependence. Cur combined with TG-520 markedly decreased the protein expression of PD-L1 (P < 0.0001), while CD4+CD25+Foxp3+ Tregs regulated by the PD-L1 signaling pathway exhibited a positive correlation with PD-L1. Cur combined with TG-520 also inhibited the cascade action mediated by NF-κB (P < 0.0001), thus inhibiting the TLR4/NF-κB signalling pathway (P = 0.0088, P < 0.0001), which is associated with inflammation and acts on PD-L1. It also inhibited the NF-κB-MMP9 signalling pathway (P < 0.0001), which is associated with tumor angiogenesis. Conclusion: Cur combined with TG regulates immune escape through the PD-L1 pathway and inhibits liver cancer growth through NF-κB-mediated inflammation and angiogenesis.
... 17-AAG has an IC 50 range of 0.1-2.37 µM, and its anticancer mechanism is the suppression of heat shock protein 90. Hence, the IC 50 of FEN indicates that the drug has sufficient anticancer efficacy [43][44][45]. The clonogenic assay confirmed the long-term inhibition of cell reproduction. ...
Article
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Fenbendazole (FEN), a broad-spectrum benzimidazole anthelmintic, suppresses cancer cell growth through various mechanisms but has low solubility and achieves low blood concentrations, which leads to low bioavailability. Solubilizing agents are required to prepare poorly soluble drugs for injections; however, these are toxic. To overcome this problem, we designed and fabricated low-toxicity Soluplus® polymeric micelles encapsulating FEN and conducted toxicity assays in vitro and in vivo. FEN-loaded Soluplus® micelles had an average particle size of 68.3 ± 0.6 nm, a zeta potential of −2.3 ± 0.2 mV, a drug loading of 0.8 ± 0.03%, and an encapsulation efficiency of 85.3 ± 2.9%. MTT and clonogenic assays were performed on A549 cells treated with free FEN and FEN-loaded Soluplus® micelles. The in vitro drug release profile showed that the micelles released FEN more gradually than the solution. Pharmacokinetic studies revealed lower total clearance and volume of distribution and higher area under the curve and plasma concentration at time zero of FEN-loaded Soluplus® micelles than of the FEN solution. The in vivo toxicity assay revealed that FEN-loaded Soluplus® micelle induced no severe toxicity. Therefore, we propose that preclinical and clinical safety and efficacy trials on FEN-loaded Soluplus® micelles would be worthwhile.
... Interestingly, bovine mammary epithelial cells (BME-UV1) proved to be more sensitive compared to BFH12 cells, as C and CL half maximal lethal concentration (LC 50 ), after 48 h of incubation, was in the range of 10-20 and 5-10 µM, respectively [20]. Overall, curcumin IC 50 has been reported to be extremely variable depending on the cell type and the time of treatment, ranging from 2 to 40 µM [61]. ...
Article
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Aflatoxin B1 (AFB1) toxicity in livestock and human beings is a major economic and health concern. Natural polyphenolic substances with antioxidant properties have proven to be effective in ameliorating AFB1-induced toxicity. Here we assessed the potential anti-AFB1 activity of curcumin (pure curcumin, C, and curcumin from Curcuma longa, CL) in a bovine fetal hepatocyte-derived cell line (BFH12). First, we measured viability of cells exposed to AFB1 in presence or absence of curcumin treatment. Then, we explored all the transcriptional changes occurring in AFB1-exposed cells cotreated with curcumin. Results demonstrated that curcumin is effective in reducing AFB1-induced toxicity, decreasing cells mortality by approximately 30%. C and CL induced similar transcriptional changes in BFH12 exposed to AFB1, yet C treatment resulted in a larger number of significant genes compared to CL. The mitigating effects of curcuminoids towards AFB1 toxicity were mainly related to molecular pathways associated with antioxidant and anti-inflammatory response, cancer, and drug metabolism. Investigating mRNA changes induced by curcumin in cattle BFH12 cells exposed to AFB1 will help us to better characterize possible tools to reduce its consequences in this susceptible and economically important food-producing species.
... La curcumine a été testée sur de nombreux modèles animaux de cancer et sur presque tous les types de cancers spécifiques d'organes, notamment le cancer du sein (Nagaraju et al., 2012 ;Sinha et al., 2012), buccal (Zlotogorski et al., 2013), les cancers du cerveau, du cou Wilken et al., 2011), le carcinome hépatocellulaire (Darvesh et al., 2012), du pancréas (Johnson and de Mejia, 2011 ;Stan et al., 2010), de la prostate (Nambiar and Singh, 2013 ;Singh and Agarwal, 2006 ;von Low et al., 2007), du colon (Sareen et al., 2013 ;Temraz et al., 2013), gastrique , ainsi que des cellules multi-drogues cancéreuses résistantes (Saha et al., 2012). Les cellules souches cancéreuses ont aussi été étudiées (Norris et al., 2013) ainsi qu'une variété d'autres cancers en chimioprévention, et chimiorésistance (Aggarwal and Gehlot, 2009 ;Aggarwal and Sung, 2009 ;Kuttan et al., 2007 ;Park et al., 2013 ;Schaffer et al., 2011 ;Sung et al., 2009). La curcumine a démontré in vivo et in vitro une capacité d'inhiber la carcinogenèse à trois stades : la promotion des tumeurs, l'angiogénèse et la croissance tumorale . ...
Thesis
La curcumine est un polyphénol de couleur jaune extrait du rhizome de la plante (Curcuma longa). Identifié comme un principe actif du curcuma, cette épice est largement consommée compte tenu de ses propriétés antioxydantes, antimicrobiennes et antitumorales. Cependant, sa solubilité et sa biodisponibilité restent limitées en raison de son hydrophobicité et diminuent de ce fait les applications potentielles dans les domaines nutraceutique et pharmaceutique. L’objectif de ce travail s’est focalisé sur l’étude des propriétés physico-chimiques de cette molécule vectorisée sous forme liposomale. Différentes formulations de nanovecteurs préparées à partir de lipides polaires plus ou moins riches en acides gras polyinsaturés à longue chaîne variables, issus de source marine ou végétale, ont été utilisées pour modifier la fluidité membranaire des vecteurs. Ces travaux ont permis d’optimiser le pourcentage d’encapsulation de cette biomolécule et d’étudier les effets de cytotoxicité et de sa biodisponibilité sur différentes lignées cellulaires (MCF7, cellules embryonnaires de neurones corticaux). Les résultats montrent des effets significatifs lors de l’utilisation de nanoliposomes formulés avec de la lécithine marine, protégés par un enrobage de polymère de chitosane. Les analyses physicochimiques de taille par diffraction de la lumière (zetasizer, nanosight), de stabilité (mesure de la taille et la mobilité électrophorétique), de structure par microscopie électronique en transmission et la libération de la molécule vectorisée, ont permis de mieux comprendre les effets des interactions polymère-phospholipides et le relargage de la curcumine encapsulée dans les conditions environnementales drastiques de digestion gastrique et intestinale. Une caractérisation multi-échelle est proposée afin d’améliorer la compréhension des différentes propriétés du nanovecteur et du principe actif qu’il vectorise, ainsi que les interactions possibles entre eux. Les techniques utilisées sont la spectroscopie infrarouge à transformée de Fourier (FTIR), les rayons X, ainsi que la microscopie électronique en transmission
... Matrix-metalloproteinases (MMPs) enhance the ability of tumor cells to penetrate cellular barriers [65]. In bladder cancer, levels of MMP-2 and MMP-9 have been shown to be diminished by curcumin with an increase of tissue inhibitor of metalloproteinase-2 (TIMP-2) as the relevant underlying mechanism. ...
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Although the therapeutic armamentarium for bladder cancer has considerably widened in the last few years, severe side effects and the development of resistance hamper long-term treatment success. Thus, patients turn to natural plant products as alternative or complementary therapeutic options. One of these is curcumin, the principal component of Curcuma longa that has shown chemopreventive effects in experimental cancer models. Clinical and preclinical studies point to its role as a chemosensitizer, and it has been shown to protect organs from toxicity induced by chemotherapy. These properties indicate that curcumin could hold promise as a candidate for additive cancer treatment. This review evaluates the relevance of curcumin as an integral part of therapy for bladder cancer.
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Oral precancerous lesions are one of the most common lesions present worldwide today. They are usually neglected by the common population when compared to cancerous lesion. However, they also may be extremely fatal which changes as cancer if left untreated at a very initial stage of the lesion. Early detection and treatment gives the best chance for its cure. The detection and diagnosis are currently based on clinical examination, histopathological evaluation. Several medications have been developed over the years for early cure of oral precancerous lesion. The purpose of this article is to review the available curcumin herbal to treat these precancerous lesions.
Article
Nano-anticancer drugs are gaining importance in cancer treatment due to their unique properties and wide range of applications. The efforts are made to synthesize silver nanoparticles by a green method and used as nano-carriers for curcumin. Green synthesis of the gum-stabilized AgNPs was monitored by UV–Vis spectrophotometry and the possible interactions of gum with AgNPs were evaluated by FT-IR. The curcumin-loaded AgNPs were characterized for their size, polydispersity index, ζ potential, morphology, size distribution, drug loading efficiency, and excipients’ interactions. The prepared nano-anticancer formulations were characterized and tested for anti-cancer potentials against MM-138, FM-55 and MCF-7 cell lines, respectively. The AgNPs acted as excellent nano-carriers for an increased amount of curcumin. In in vitro anticancer study, the IC50 values for AgNPs, curcumin, and curcumin-loaded AgNPs were 166.3, 82.2 and 61.6 µg/mL; 153.2, 107.3 and 77.1 µg/mL; and 144.6, 81.2 and 60.6 µg/mL against MM-138, FM-55 and MCF-7 cell lines, respectively. It was observed that silver nanoparticles showed good loading capacity for curcumin. Also, the curcumin-loaded nanoparticles showed good anticancer activities against MM-138, FM-55 and MCF-7 cell lines, respectively. The reported nano-anticancer drug formulations may be tested in vivo studies and clinical trials for treating cancer in the future.
Chapter
Natural or chemically modified dietary phytochemicals are particularly favored for cancer prevention because they can reverse, suppress, or prevent the initial phase of carcinogenesis or the neoplastic cell progression to cancer mass, and therefore, eliminate premalignant and malignant cell populations either in general or in high-risk populations. Screening and identifying dietary phytochemicals for chemoprevention requires in vitro studies of cell lines and animal models before translation into clinical trials. Understanding the molecular pathways that dietary phytochemicals modify could help in designing successful cancer prevention clinical trials. To date, a number of chemoprevention clinical trials have been conducted with limited success. One of the reasons for unsuccessful clinical trials was the lack of a clear molecular target against a particular cancer type. High-throughput screening of phytochemicals to induce premalignant and malignant cell apoptosis by targeting multiple gene pathways should be assessed for future prevention of human cancers.
Chapter
There has been a significant scientific spotlight on curcumin (diferuloylmethane) in recent years, with studies investigating its potential health benefits. As a result, curcumin has been linked to a range of health benefits, including potential protection against cancer, Alzheimer’s disease, Parkinson’s disease, heart failure, diabetes, arthritis, and many more. Curcumin has been researched for biological activities, disease prevention, and treatment. Curcumin is a hydrophobic polyphenol extracted from rhizome (turmeric) of the herb Curcuma longa. It is poorly absorbed following oral route and highly metabolized via enterohepatic bypass effect. Few novel formulations of curcumin and its derivatives have been explored and developed to overcome the limitation of achieving high plasma levels. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human diseases.
Article
Objective: The aimed of this study was to evaluate Ethanolic turmeric extracts (ETE) as anticancer agent by detect the apoptotic induction and DNA damage activity of ETE which were investigated against two human leukemic cell lines, U937 (human monocytic leukemia cell line) and Molt4 (human lymphoblastic cell line). Methods: ETE obtained by extraction of turmeric by ethanol solvent, apoptosis activity was performed by using 4, 6-diamidino-2-phenylindole di-hydrochloride [DAPI] stain; also comet assay which is sensitive method of detection double strand break (DSB) of DNA was used. Results: showed that apoptotic activity of ETE against U937, Molt4 cell lines were 58.06% and 39.07% respectively while apoptotic activity of Melphalan were 92.04% and 89.03% respectively by using DAPI stain, otherwise apoptotic percentage of ETE were 92.44% and 61.95% against U937, Molt4 respectively while by Melphalan were 100% against both of leukemic cell lines which evaluated by comet assay. Conclusion: Ethanolic turmeric extracts (ETE) showed that have apoptogenic and DNA damage activity against two human leukemic cell lines. Otherwise DAPI stain and comet assay prove to be suitable tools to detect DNA damage of U937 and Molt4 leukemic cell lines by ETE.
Article
Cancer occurs as a result of alterations in oncogenes, tumor-suppressor genes, and microRNA genes. Over the past few decades, efforts have been made to understand the dominant oncogenes and tumor suppressor genes whose respective activation/upregulation or loss of function serve to impart aberrant properties on normal cells. The most common types include but are not limited to lung, prostate, colorectal, breast, ovarian and skin cancers and leukemia. Less common but equally deadly is the squamous cell carcinoma of the oropharynx. In 2012, there were more than 8 million deaths worldwide related to cancer from 14 million new cases. Cancer chemotherapy frequently requires long periods of multiple intravenous infusions which may compel patients to abandon treatment. One approach to overcome this challenge is through the use of transdermal drug delivery systems. The major obstacle with transdermal drug delivery is that the stratum corneum, which is the outermost layer of the skin, hinders the penetration of therapeutic agents. An avalanche of techniques is available to enhance the penetration of anticancer agents across the skin including iontophoresis, sonophoresis, microneedles, prodrugs, microemulsions and elastic liposomes. In this review, attention is focused on the numerous techniques used to overcome the skin barrier and enhance the percutaneous penetration of anticancer agents.
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Esta investigación cualitativa etnográfica tuvo como objetivos describir, analizar y comprender el cuidado cultural en el hogar de mujeres con cáncer de mama en el distrito de Chiclayo. La muestra fue obtenida por la técnica de saturación y redundancia, conformado por 11 mujeres que reciben quimioterapia en el Hospital Regional de Lambayeque, previo consentimiento informado, a quienes se les aplicó la entrevista etnográfica y observación participante. Los datos obtenidos se procesaron mediante el análisis de contenido temático según Spradley, emergiendo 4 temas: Los remedios caseros, una alternativa importante en el cuidado cultural del cáncer de mama; cuidado cultural en el tratamiento de los principales efectos adversos de la quimioterapia; inmersión en el cuidado, en s nueva etapa de vida y la espiritualidad como cuidado cultural para afrontar el cáncer de mama. Concluyendo que los cuidados culturales de las mujeres con cáncer de mama son principalmente el uso de remedios caseros, como el uso de plantas medicinales, por ejemplo, la flor de overo, la hoja de menta, la semilla de calabaza o la cúrcuma. Se tomaron en cuenta los principios éticos y de rigor científico.
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The last few years have seen the intensive investigation efforts for understanding the wide relevance of AXL activation in multiple aspects of oncogenesis, invasion, metastasis and drug resistance. Therfore, targeting AXL can be considered as one of the promissing approaches for the treatement of cancer. A series of curcumin derivatives which are natural polyphenolic coumponds were wellreported as an anti cancer and chemopreventive agents. We have investigated them as an ATP-competitive inhibitors of AXL kinase by using a docking studies. We built a model of AXL catalytic domain from the crystal structure of proto-oncogene tyrosine-protein kinase MER (MERTK) and the modeling of the three-dimensional (3D) structure of the AXL was performed by SWISS-MODEL homology modeling program. The quality and validation of the model were performed using PROCHECK and VERIFY 3D softwares. The Ramachandran plot was used to validate the overall stereochemical property of the protein. All curcuminoids formed a hydrogen bond with hinge region by Methionine (Met 623) and lysine (Lys 567) indicating that these comp
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In summary, we have developed a glycyrrhetinic acid-modified curcumin supramolecular pro-gelator (GA-Cur), which could be converted to a supramolecular hydrogelator and form a hydrogel (GA-Gel) by disulfide bond reduction by GSH. Curcumin could be sustainedly released from the GA-gel through ester bond hydrolysis. Compared with curcumin and Nap-Cur, GA-Cur had more potent anti-cancer efficacy and higher cellular uptake for GA positive tumor cells in vitro. In conclusion, GA-Cur is a promising and potential therapeutic option for hepatocellular carcinoma therapy.
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Curcumin was found to be beneficial in treating several skin pathologies and diseases, providing antioxidant protection due to its reducing properties and its electrophilic properties (the ability to activate the Nrf 2 pathway and induce phase II cytoprotective enzymes). Nevertheless, clinical applications of curcumin are being hampered by its insufficient solubility, chemical instability, and poor absorption, leading to low efficacy in preventing skin pathologies. These limitations can be overcome by using a nanotechnology-based delivery system. Here, we elucidated the possibility of using curcumin encapsulated in a microemulsion preserving its unique chemical structure. We also examined whether curcumin microemulsion would reduce UVB-induced toxicity in skin. A significant curcumin concentration was found in the human skin dermis following topical application of a curcumin microemulsion. Moreover, curcumin microemulsion enhanced the reduction of UV-induced cytotoxicity in epidermal cells, paving the way for other incorporated electrophiles in encapsulated form protecting skin against stress-related diseases.
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Objective: Gastric cancer is one of the most common causes of cancer-related death worldwide. Medicinal plants are one of the main sources for discovery of new pharmacological agents especially for treatment of cancers. The aim of the present study is to review pharmacotherapeutic aspects of three mostly studied phytochemicals including curcumin, quercetin, and allicin for management of gastric cancer. Methods: Scopus, PubMed, Web of Science, and Google Scholar were searched for the effects of curcumin, quercetin, allicin, and their analogs in gastric cancer. Data were collected up to November 2015. The search terms were "curcumin," "quercetin," "allicin," and "gastric cancer" or "cancer." Results: Curcumin demonstrated anti-angiogenic, anti-proliferative, anti-metastatic, pro-apoptotic, and anti-helicobacter activities. Quercetin inhibited cell growth and induced apoptosis, necrosis, and autophagy as well as anti-Helicobacter activity. Allicin showed apoptotic and anti-Helicobacter properties. All three natural compounds had low bioavailability. Conclusions: Although preclinical studies demonstrated the activity of curcumin, quercetin, and allicin in gastric cancer, clinical trials are needed to confirm their effectiveness. Applying their possible synergistic action and suitable drug delivery system in clinical studies can be also an attractive approach with the purpose of finding new extremely efficient anti-gastric cancer agents. Curcumin, quercetin, and allicin seem to be good candidates for management of gastric cancer through their pro-apoptotic, anti-proliferative, and anti-helicobacter activities.
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The sweet chestnut (Castanea sativa Mill.) and European beech (Fagus sylvatica L.) are wood species largely present in the European forest area. The composition and relative variation of the secondary metabolites of chestnut and European beech wood under thermal effect is a little-explored area. The wood material was thermally modified at 170 °C for 3 h using a thermo-vacuum technology. Raw and modified wood extracts were obtained with aqueous extraction techniques in an autoclave, subsequently lyophilized, solubilized in ethyl acetate, and determined by Gas Chromatographic-Mass Spectrometric Analyses (GC-MS). In addition, the volatile compounds were determined by Solid-Phase Micro Extraction (SPME) analyses. As a general statement, the extraction in an autoclave produced a higher number of compounds in the modified chestnut and beech wood compared to unmodified wood material. Beech wood showed low degradation in the compounds after modification. Notably, squalene and ar-tumerone were the main bioactive compounds present in beech wood extractives. Chestnut, conversely, showed a greater degradation after thermo-modification. However, a reduction in chemical compounds in the modified samples was also observed. In this case, the main biologically active compounds detected only in the chestnut control samples were apocynin and ar-tumerone. The recovery of this residual wood material, before energy consumption, could provide a sustainable and environmentally friendly means of obtaining natural chemicals suitable for various industrial applications.
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Sophorolipid biosurfactants are biodegradable, less toxic and FDA approved. The purified acidic form of sophorolipid is stimuli-responsive with self-assembling properties and used for solubilizing hydrophobic drugs. This study encapsulated curcumin (CU) with acidic sophorolipid (ASL) micelles and analysed using photophysical studies like UV-visible spectroscopy, photoluminescence (PL) spectroscopy and time-correlated single photon counting (TCSPC). TEM images have revealed ellipsoid micelles of approximately 100 nm size and were confirmed by dynamic light scattering. The bacterial fluorescence uptake studies showed the uptake of formed CUASL nanostructures into both Gram-positive and Gram-negative bacteria. They also showed quorum quenching activity against Pseudomonas aeruginosa. The results have demonstrated this system has potential theranostic applications.
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The eradication of cancer in a patient remains an elusive challenge despite advances in early detection and diagnosis, chemo- and immunotherapy, pinpoint radiation treatments, and expert surgical intervention. Although significant gains have been made in our understanding of cancer cell biology, a definite cure for most cancers does not exist at present. Thus, it is not surprising that the research and medical communities continue to explore the importance and therapeutic potential of natural products in their multimodality cancer treatment approach. Curcuminoids found in turmeric are one such class of natural products that have been extensively investigated for their potential to halt the progression of cancer cell proliferation and, more important, to stop metastasis from occurring. In this review, we examine one curcuminoid (demethoxycurcumin [DMC]) largely because of its increased stability and better aqueous solubility at physiological pH, unlike the more well-known curcuminoid (curcumin), which is largely unabsorbed after oral ingestion. The present review will focus on the signaling pathways that DMC utilizes to modulate the growth, invasion, and metastasis of cancer cells in an effort to provide enhanced mechanistic insight into DMC's action as it pertains to brain, ovarian, breast, lung, skin, and prostate cancer. Additionally, this review will attempt to provide an overview of DMC's mechanism of action by modulating apoptosis, cell cycle, angiogenesis, metastasis, and chemosensitivity. Lastly, it is hoped that increased understanding will be gained concerning DMC's interactive role with microRNA-551a, 5' adenosine monophosphate-activated protein kinase, nuclear factor-κB, Wnt inhibitory factor-1, and heat shock protein 70 to affect the progression of cancer.
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A new curcuminoid, cyclocurcumin (IV), was isolated from the nematocidally active fraction of turmeric, the rhizome of Curcuma longa, together with three known curcuminoids, curcumin (I), demethoxycurcumin (II) and bisdemethoxycurcumin (III). The structure of IV was elucidated on the basis of spectral data and confirmed by the partial synthesis from curcumin (I). Although the above curcuminoids were ineffective when they were applied independently, the nematocidal activity increased remarkably when they were mixed, suggesting a synergistic action between them.
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Brown Norway rats were primed intraperitoneally) with β-lactoglobulin for 3wk to induce reaginic antibody, during which time they were fed diets containing 10% each of coconut oil (CO), high oleic safflower oil, safflower oil (SO), or fish oil, then they were challenged for 3h orally with the antigen. The dietary SO, compared to other dietary fats, resulted in lower circulatory release of rat chymaseII (RChyII), an indicator of degranulation of mucosal mast cells in the intestine, in response to the antigen. Addition of 0.5% curcumin to the CO or SO diet lowered the release. The SO diet, compared to CO diet, tended to increase the concentration of reaginic antibody, but the influence of curcumin addition was not prominent. These results indicate that dietary ingredients differently influence the synthesis of immunoglobulin E and degranulation of mast cells.
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Products of arachidonic acid metabolism can influence normal and malignant cell growth. In vivo, inhibitors of arachidonic acid metabolism have been associated with inhibition of tumor growth, including head and neck squamous cell carcinoma (HNSCC). This has not been evaluated extensively in vitro in an HNSCC model. Therefore we investigated the effects of several arachidonic acid cascade inhibitors (AACIs) (indomethacin, curcumin, phenidone, nordihydroguaiaretic acid, 5,8,11, 14-eicosatetraynoic acid, and 13-cisretinoic acid) on the growth of two HNSCC cell lines (MDA 886 Ln and 1483). We found that AACIs caused dose-dependent growth inhibition of both cell lines. In an effort to inhibit HNSCC cell growth at lower concentrations of these drugs, we evaluated the effects of a variety of AACIs in combination with 13-cis retinoic acid. We observed synergistic growth inhibition when the drugs were used in all combinations, with the exception of indomethacin. These results suggest that AACIs may have some utility in the direct treatment of HNSCC, and a strategy combining 13-cis retinoic acid with other AACIs may prove to be even more effective.
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It has been well known that curcumin is a powerful inhibitor of proliferation of several tumor cells. However, the molecular basis of the anti-proliferative effect of curcumin has not been investigated in detail. In this paper, we present evidence to show that curcumin inhibited proliferation of a variety of B lymphoma cells. At low concentrations curcumin inhibited the proliferation of BKS-2, an immature B cell lymphoma, more effectively than that of normal B lymphocytes and caused the apoptosis of BKS-2 cells in a dose- and time-dependent manner. Furthermore, curcumin downregulated the expression of survival genes egr-1, c-myc, and bcl-XL as well as the tumor suppressor gene p53 in B cells. In addition, NF-κB binding activity was also downregulated almost completely by curcumin. Stimulation with CpG oligonucleotides or anti-CD40 overcame growth inhibition induced by low concentrations of curcumin. Our results suggest that curcumin caused the growth arrest and apoptosis of BKS-2 immature B cell lymphoma by downregulation of growth and survival promoting genes.
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Chronic administration of carbon tetrachloride caused liver fibrosis in rats. Carbon tetrachloride-induced fibrosis was found to significantly elevate the marker enzymes, serum transaminases and alkaline phosphatase as well as lipid peroxidation end product, malondialdehyde or thiobarbituric acid reactive substance in the liver. Fibrosis also caused increase in the serum and tissue cholesterol and decreased tissue phospholipids and free fatty acids. Histopathological examinations also confirm the severe hepatological damage occurred as a consequence of carbon tetrachloride-induced fibrosis. Treatment of curcumin to the fibrotic rats showed a significant improvement after hepatic damage as well as restoration of lipid profile, marker enzymes and thiobarbituric acid reactive substances towards normal.
Alzheimer's disease (AD) is believed to involve increased soluble but toxic beta amyloid (A) peptide aggregates, leading to the accumulation of insoluble A deposits, inflammation, oxidative damage, tau pathology and ultimately cognitive deficits. Blocking A formation early should prevent AD, but most interventions are likely to occur after seeding of deposits and tangles and after initiation of the amyloid cascade. In order to identify agents that might suppress both amyloid and the response to amyloid in vivo, we infused toxic soluble A into rat ventricles and screened agents targeting amyloid, oxidative damage and inflammation. The combined NSAID / antioxidant curcumin was found to be most efficacious in reducing amyloid, oxidative damage, inflammation and synaptic marker loss. Similar curcumin benefits were then shown in APPsw transgenic mice. One central mechanism underlying curcumin's reductions in soluble and guanidine-extracted insoluble A appears to be stimulation of phagocytic clearance pathways. Curcumin stimulates amyloid phagocytosis and clearance while exerting net anti-inflammatory activity. Because curcumin and its derivatives (curcuminoids) also protect against the response to amyloid, particularly the oxidative damage and resulting synaptic loss, they appear well suited for AD treatment. Evidence also supports curcumin effects on reducing A aggregation and lowering cholesterol. Low cost, low dose efficacy, low toxicity and multiple potential protective activities make curcumin and its derivatives strong candidates for AD prevention.
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Diabetes mellitus is one of the most common endocrine disorders. A large number of studies are in progress to identify natural substances that are effective in reducing the severity of diabetes. Although a number of drugs are currently marketed, their long-term use can cause a number of adverse effects. In the present study, we examined the effect of photo-irradiated curcumin on experimental diabetes in order to evaluate the antihyperglycaemic effects of this compound on streptozotocin (40 mg/kg bodyweight)-induced diabetes. Photo-irradiated curcumin was given at a dose of 10, 30 and 80 mg/kg bodyweight. The level of blood glucose was elevated in the diabetic animals. The liver, kidney and brain were assayed for the degree of lipid peroxidation, reduced glutathione content and the activity of enzymic and levels of non-enzymic antioxidants. Antioxidant status decreased in the diabetic animals. Oral administration of photo-irradiated curcumin for 45 days resulted in a significant decrease in the levels of blood glucose, together with near normalisation of enzymic activity and the markers of lipid peroxidation. The best results were obtained in rats treated with 30 mg/kg bodyweight of photo-irradiated curcumin.
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Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.
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Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC50 values of 9.42 and 19.5 μM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 μM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action. Keywords: Garcinol; curcumin; apoptosis; cytochrome c; caspase-9; caspase-2; caspase-3; poly(ADP-ribose) polymerase; DNA fragmentation factor; caspase-activated deoxyribonuclease
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Antioxidant mechanisms of curcumin, bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, have been studied by laser flash photolysis and pulse radiolysis. The keto−enol−enolate equilibrium of the heptadienone moiety of curcumin determines its physicochemical and antioxidant properties. In neutral and acidic aqueous solutions (from pH 3 to 7), the keto form dominates, and curcumin acts as an extraordinarily potent H-atom donor. The reaction rate constant with the methyl radical (3.5 ± 0.3) × 109 M-1 s-1 is close to diffusion control in 40% aqueous DMSO at pH 5. The tert-butoxyl radical reacts with curcumin in acetonitrile solutions at a diffusion controlled rate, k = (7.5 ± 0.8) × 109 M-1 s-1. The apparent site of reaction is the central CH2 group in the heptadienone link, which has two labile hydrogens. This is supported by comparing the reaction patterns of curcumin and dehydrozingerone (DHZ) (“half-curcumin”, 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one). DHZ does not react with the methyl radical, indicating that the presence of the labile hydrogens is crucial for the H-atom donating ability of curcumin. The tert-butoxyl radical reacts with DHZ at almost an order of magnitude lower rate (1.1 ± 0.1) × 109 M-1 s-1, clearly abstracting an H-atom from the phenolic OH group. The reaction mechanism of curcumin changes dramatically above pH 8, where the enolate form of the heptadienone link predominates. As a consequence, the reaction of the methyl radical diminishes completely in alkaline media, and the phenolic part of the molecule takes over as (electron donor) reaction site. The electron donating ability of curcumin is assessed from the measurements of one-electron-transfer equilibria of DHZ radicals. Reduction potential of the DHZ phenoxyl radical, E(pH = 6.5) = 0.83 ± 0.06 V, and E(pH = 13.0) = 0.47 ± 0.06 V vs NHE, which may be expected for an ortho-methoxy-substituted phenoxyl radical, indicate only moderate electron-donating ability. The importance of H-atom donation vs electron donation in free radical scavenging and antioxidant mechanisms of curcumin is discussed.
Article
Objective To investigate the roles of tumor necrosis factor (TNF) and the CD40–CD154 interaction in interleukin-12 (IL-12) production by rheumatoid synovial cells (SC).Methods Levels of IL-12 (p40 and p70) in synovial tissue and culture supernatants of SC from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and ankylosing spondylitis (AS) were assayed by enzyme-linked immunosorbent assay. Effects of anti-CD154 and anti-TNF antibody on spontaneous and lipopolysaccharide (LPS)–stimulated IL-12 production by SC were examined. Effects of immobilized anti-CD3 treatment and depletion of CD4+ T cells on IL-12 production were also tested. CD154 expression by synovial T cells and intracellular IL-12 production during culture were analyzed by flow cytometry.ResultsIL-12 p40 and p70 levels in RA synovial tissue and spontaneous IL-12 p40 production by SC from RA patients were significantly higher than the levels in OA and AS patients. Spontaneous IL-12 production by SC from RA patients significantly decreased after depletion of CD4+ T cells from SC or after application of anti-CD154 antibody, but not by treatment with anti-TNF antibody. Anti-CD3 antibody stimulation increased spontaneous IL-12 p40 production and CD154 expression by synovial T cells. The increment of IL-12 p40 production by anti-CD3 was abrogated by anti-CD154 antibody. IL-12 p40 production was also increased by LPS stimulation. LPS-stimulated IL-12 production was inhibited by anti-TNF antibody, but not by T cell depletion and anti-CD154 antibody treatment. The TNF inhibitor rolipram inhibited LPS-stimulated IL-12 p40 production by RA SC more strongly than spontaneous production. TNF restored LPS-stimulated IL-12 production that had been inhibited by rolipram.ConclusionIL-12 production in RA is regulated by 2 different pathways. One pathway is T cell dependent, predominantly through a CD40–CD154 interaction, while the other is T cell independent, mediated through TNF. Inhibition of IL-12 production by interference with CD40–CD154 interaction and TNF production may be a potential therapeutic strategy for treating RA.
Human population can be considered as a subject of combined exposure to chemicals. Hexavalent chromium is a well-known mutagen and carcinogen. Curcumin, a popular spice and pigment, is reported to have antineoplastic properties. The single cell gel electrophoresis (Comet assay) is a sensitive technique that allows detecting double- and single-strand DNA breaks caused by a broad spectrum of mutagens. In the present work the ability of curcumin to reduce DNA damage induced by chromium in human lymphocytes and gastric mucosa (GM) cells was investigated by using the comet assay. Chromium at 500 μM evoked DNA damage measured as significant (P < 0.001), about a two-fold increase in comet tail moment of both lymphocytes and GM cells. Curcumin at 10, 25, and 50 μM also damaged DNA of both types of cells in a dose-dependent manner: the increase in the tail moment reached about twenty times of the control value (P < 0.001). The combined action of chromium at 500 μM and curcumin at 50 μM resulted in the significant (P < 0.001) increase in the comet tail moment of both types of cells. In each case, treated cells were able to recover within 60 min. Our study clearly demonstrates that curcumin does not inhibit DNA damaging action of hexavalent chromium in human lymphocytes and GM cells. Moreover, curcumin itself can damage DNA of these cells and the total effect of chromium and curcumin is additive. Further studies are needed to establish the role of interaction of curcumin with DNA in carcinogenesis. Teratogenesis Carcinog. Mutagen. 19:19–31, 1999. © 1999 Wiley-Liss, Inc.
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We have evaluated the comparative effect of curcumin (diferuloyl methane) and its analogue [bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione] (BDMC-A) on carbon tetrachloride-induced hepatotoxicity in rats. Administration of carbon tetrachloride (3 ml/kg/week) for three months significantly (P<0.05) increased the levels of marker enzymes such as aspartate transaminase (AST), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT). The levels of plasma thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides were also significantly (P<0.05) increased. We have observed a significant (P<0.05) decrease in the levels of plasma reduced glutathione (GSH), vitamin C and vitamin E. There was a significant (P<0.05) increase in the levels of TBARS and hydroperoxides in liver and kidney and a significant (P<0.05) decrease in the activities of enzymic antioxidants- superoxide dismutase (SOD), catalase and GSH peroxidase along with GSH in CCl4-treated rats. Oral administration of curcumin and BDMC-A to CCl4-induced rats for a period of three months significantly (P<0.05) decreased the levels of marker enzymes, plasma TBARS and hydroperoxides and increased the levels of plasma and tissue antioxidants. Histopathological studies of liver also showed protective effect of curcumin and BDMC-A. We have observed thickening of blood vessels and microvesicular fatty changes around the portal triad in CCl4-treated rat liver. Treatment with curcumin showed only mild sinusoidal dilatation while with BDMC-A there was only mild portal inflammation. The effect exerted by BDMC-A was found to be more promising than curcumin.
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