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Journal ArticleDOI

Curcumin induces stress response, neurite outgrowth and prevent NF-kappaB activation by inhibiting the proteasome function.

01 Jan 2006-Neurotoxicity Research (Neurotox Res)-Vol. 9, Iss: 1, pp 29-37
TL;DR: It is shown that curcumin disrupts UPS function by directly inhibiting the enzyme activity of the proteasome’s 20S core catalytic component, which causes an increase in half-life of IκB-α that ultimately leads to the down-regulation of NF-κB activation.
Abstract: Curcumin, a natural polyphenolic compound, has long been known as an anti-tumour and anti-inflammatory compound; although, the common mechanism through which it exhibits such properties are remains unclear. Recently, we reported that the curcumin-induced apoptosis is mediated through the impairment of ubiquitin proteasome system (UPS). Here, we show that curcumin disrupts UPS function by directly inhibiting the enzyme activity of the proteasome's 20S core catalytic component. Like other proteasome inhibitors, curcumin exposure induces neurite outgrowth and the stress response, as evident from the induction of various cytosolic and endoplasmic reticulum chaperones as well as induction of transcription factor CHOP/GADD153. The direct inhibition of proteasome activity also causes an increase in half-life of IkappaB-alpha that ultimately leads to the down-regulation of NF-kappaB activation. These results suggest that curcumin-induced proteasomal malfunction might be linked with both anti-proliferative and anti-inflammatory activities.
Citations
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Journal ArticleDOI
TL;DR: A better understanding of the neurotrophic effects of polyphenols and the concomitant modulations of signaling pathways is useful for designing more effective agents for management of neurodegenerative diseases.
Abstract: Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer's and Parkinson's disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk) receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Finally, the antioxidant activity of polyphenols reflected in the activation of Nrf2 pathway and the consequent upregulation of detoxification enzymes such as heme oxygenase-1 as well as the contribution of these effects to the neurotrophic activity have also been discussed. In conclusion, a better understanding of the neurotrophic effects of polyphenols and the concomitant modulations of signaling pathways is useful for designing more effective agents for management of neurodegenerative diseases.

208 citations


Cites background from "Curcumin induces stress response, n..."

  • ...Moreover, curcumin did not interfere with the cisplatin’s antitumor mode of action as assessed in vitro in HepG2 cells.(87)...

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Journal ArticleDOI
TL;DR: Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases.
Abstract: Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin.

200 citations


Cites background from "Curcumin induces stress response, n..."

  • ...The curcumin-induced proteasomal malfunction might be linked with both antiproliferative and anti-inflammatory activities [74]....

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Book ChapterDOI
TL;DR: Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects, which include the regulation of signal transduction pathways and direct modulation of several enzymatic activities.
Abstract: Curcumin is the active ingredient of turmeric that has been consumed as a dietary spice for ages. Turmeric is widely used in traditional Indian medicine to cure biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. Extensive investigation over the last five decades has indicated that curcumin reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms associated with type II diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, inhibits HIV replication, enhances wound healing, protects from liver injury, increases bile secretion, protects from cataract formation, and protects from pulmonary toxicity and fibrosis. Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects. These include the regulation of signal transduction pathways and direct modulation of several enzymatic activities. Most of these signaling cascades lead to the activation of transcription factors. Curcumin has been found to modulate the activity of several key transcription factors and, in turn, the cellular expression profiles. Curcumin has been shown to elicit vital cellular responses such as cell cycle arrest, apoptosis, and differentiation by activating a cascade of molecular events. In this chapter, we briefly review the effects of curcumin on transcription factors NF-KB, AP-1, Egr-1, STATs, PPAR-gamma, beta-catenin, nrf2, EpRE, p53, CBP, and androgen receptor (AR) and AR-related cofactors giving major emphasis to the molecular mechanisms of its action.

192 citations

Journal ArticleDOI
TL;DR: The diverse molecular mechanism(s) by which the NF-κB pathway is constitutively activated in different types of human cancers, and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression are highlighted.
Abstract: The transcription factor nuclear factor kappa B (NF-κB) has attracted increasing attention in the field of cancer research from last few decades. Aberrant activation of this transcription factor is frequently encountered in a variety of solid tumors and hematological malignancies. NF-κB family members and their regulated genes have been linked to malignant transformation, tumor cell proliferation, survival, angiogenesis, invasion/metastasis, and therapeutic resistance. In this review, we highlight the diverse molecular mechanism(s) by which the NF-κB pathway is constitutively activated in different types of human cancers, and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. Additionally, various pharmacological approaches employed to target the deregulated NF-κB signaling pathway, and their possible therapeutic potential in cancer therapy is also discussed briefly.

158 citations


Cites background from "Curcumin induces stress response, n..."

  • ...2006) or disrupting the function of the ubiquitin proteasome system (Dikshit et al. 2006)....

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  • ...In addition, some studies suggested that curcumin downregulates NF-κB activation by inhibiting Notch-1 signaling (Wang et al. 2006) or disrupting the function of the ubiquitin proteasome system (Dikshit et al. 2006)....

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Journal ArticleDOI
TL;DR: It was shown that curcumin inhibits invasion and proliferation of cervical cancer cells via impairment of NF-kB and Wnt/β-catenin pathways, proposing further studies on the potential impacts of this compound on cancer therapy.
Abstract: Curcumin is a natural non-toxic phenol which is isolated from Curcumin longa L. Mounting evidence has revealed the anticancer properties of curcumin in various tumors, but the underlying molecular mechanisms of this suppression in cervical cancer is still remained unclear. Here we assessed the antitumor effects of curcumin compared with 5-Fluorouracil in Hella cells in spheroids models and monolayer cell cultures. The anti-proliferative effects of curcumin and 5-Fluorouracil were as examined in spheroid and monolayer models. The expression levels of Wnt/β-catenin and NF-kB pathways as well as the influence of the cell cycle were evaluated. Curcumin inhibited cell growth in Hella cells through the regulation of NF-kB and Wnt pathways. Also, cells developed a G2/M cell cycle arrest followed by sub-G1 apoptosis with 5-Fluorouracil and curcumin. It was also shown that curcumin either considerably affects the Wnt/β-catenin and NF-kB pathways. We showed that curcumin inhibits invasion and proliferation of cervical cancer cells via impairment of NF-kB and Wnt/β-catenin pathways, proposing further studies on the potential impacts of this compound on cancer therapy.

156 citations

References
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Journal ArticleDOI
TL;DR: It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease.
Abstract: Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, conside...

3,990 citations

Journal Article
TL;DR: Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis, and Pharmacologically,Curcumin has been found to be safe.
Abstract: Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF- κB, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. Curcumin, derived from turmeric (vernacular name: Haldi), is a rhizome of the plant Curcuma longa. The medicinal use of this plant has been documented in Ayurveda (the Indian

2,453 citations

Journal ArticleDOI
TL;DR: It appears that when given orally, curcumin is far less active than after i.p. administration, and systemic effects seem to be questionable after oral application except that they occur at very low concentrations ofCurcumin, which does not exclude a local action in the gastrointestinal tract.
Abstract: The data reviewed indicate that extracts of Curcuma longa exhibit anti-inflammatory activity after parenteral application in standard animal models used for testing anti-inflammatory activity It turned out that curcumin and the volatile oil are at least in part responsible for this action It appears that when given orally, curcumin is far less active than after ip administration This may be due to poor absorption, as discussed Data on histamine-induced ulcers are controversial, and studies on the secretory activity (HCl, pepsinogen) are still lacking In vitro, curcumin exhibited antispasmodic activity Since there was a protective effect of extracts of Curcuma longa on the liver and a stimulation of bile secretion in animals, Curcuma longa has been advocated for use in liver disorders Evidence for an effect on liver disease in humans is not yet available From the facts that after oral application only traces of curcumin were found in the blood and that, on the other hand, most of the curcumin is excreted via the faeces it may be concluded that curcumin is absorbed poorly by the gastrointestinal tract and/or underlies presystemic transformation Systemic effects therefore seem to be questionable after oral application except that they occur at very low concentrations of curcumin This does not exclude a local action in the gastrointestinal tract

1,714 citations

Journal ArticleDOI
TL;DR: It is demonstrated that curcumin (diferuloylmethane), a known anti-inflammatory and anticarcinogenic agent, is a potent inhibitor of NF-κB activation.

1,326 citations

Journal ArticleDOI
TL;DR: The molecular sequelae of PS-341 treatment in MM cells are characterized and the rationale for future clinical trials of this promising agent, in combination with conventional and novel therapies, to improve patient outcome in MM is explained.
Abstract: The proteasome inhibitor PS-341 inhibits IκB degradation, prevents NF-κB activation, and induces apoptosis in several types of cancer cells, including chemoresistant multiple myeloma (MM) cells. PS-341 has marked clinical activity even in the setting of relapsed refractory MM. However, PS-341-induced apoptotic cascade(s) are not yet fully defined. By using gene expression profiling, we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on molecular pathways responsible for the anticancer actions of this promising agent. The transcriptional profile of PS-341-treated cells involved down-regulation of growth/survival signaling pathways, and up-regulation of molecules implicated in proapoptotic cascades (which are both consistent with the proapoptotic effect of proteasome inhibition), as well as up-regulation of heat-shock proteins and ubiquitin/proteasome pathway members (which can correspond to stress responses against proteasome inhibition). Further studies on these pathways showed that PS-341 decreases the levels of several antiapoptotic proteins and triggers a dual apoptotic pathway of mitochondrial cytochrome c release and caspase-9 activation, as well as activation of Jun kinase and a Fas/caspase-8-dependent apoptotic pathway [which is inhibited by a dominant negative (decoy) Fas construct]. Stimulation with IGF-1, as well as overexpression of Bcl-2 or constitutively active Akt in MM cells also modestly attenuates PS-341-induced cell death, whereas inhibitors of the BH3 domain of Bcl-2 family members or the heat-shock protein 90 enhance tumor cell sensitivity to proteasome inhibition. These data provide both insight into the molecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of PS-341, in combination with conventional and novel therapies, to improve patient outcome in MM.

763 citations