Article

Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of I??B kinase and nuclear factor ??B activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway

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Abstract

Nuclear factor-kappaB (NF-kappaB) plays a central role in cell survival and proliferation in human melanoma; therefore, the authors explored the possibility of exploiting NF-kappaB for melanoma treatment by using curcumin, an agent with known, potent, NF-kappaB-inhibitory activity and little toxicity in humans. Three melanoma cell lines (C32, G-361, and WM 266-4), all of which had B-raf mutations, were treated with curcumin, and the authors assessed its effects on viability ((3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay) and apoptosis (flow-cytometric analysis of annexin V/propidium iodide-stained cells). Curcumin-treated cells also were examined for NF-kappaB binding activity (electrophoretic mobility shift assay) and for the activity of its upstream regulator, IkappaB kinase (IKK) (immune complex kinase assay). In addition, relevant signaling, as reflected by B-Raf kinase activity (kinase cascade assay), and steady-state levels of activated, downstream effectors, as reflected by mitogen-activated signal-regulated protein kinase (MEK), extracellular signal-regulated protein kinase (ERK), and Akt phosphorylation levels (immunoblots), were assessed. Curcumin treatment decreased cell viability of all 3 cell lines in a dose-dependent manner (50% inhibitory concentration = 6.1-7.7 microM) and induced apoptosis. NF-kappaB and IKK were active constitutively in all melanoma cell lines examined, and curcumin, under apoptosis-inducing conditions, down-regulated NF-kappaB and IKK activities. However, curcumin did not inhibit the activities of B-Raf, MEK, or ERK, and Akt phosphorylation was enhanced. Furthermore, in the presence of curcumin, the Akt inhibitor 1L-6-hydroxymethyl-chiro-inositol 2-[(R)-2-O-methyl-3-O-octadecylcarbonate] no longer suppressed Akt phosphorylation. Curcumin has potent antiproliferative and proapoptotic effects in melanoma cells. These effects were associated with the suppression of NF-kappaB and IKK activities but were independent of the B-Raf/MEK/ERK and Akt pathways.

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... Curcumin is effective in preventing cognitive impairment in Alzheimer Disease, Parkinson Disease and oxidative stress related pathologies due to its antioxidative, anti-inflammatory roles [1,2]. Modern study reveals curcumin for its antioxidant [3], anti-inflammatory [4], antitumor [5] and antiangiogenic [6] properties. These properties are attributed to the key elements in the curcumin structure [7,8]. ...
... These properties are attributed to the key elements in the curcumin structure [7,8]. Curcumin has found significant preventive against Aβ aggregation [6,[9][10][11][12], the major threats for memory loss. Systematic study of curcumin also confirms its biological utility as antimicrobial activity [13,14]. ...
... The IR spectra of the compounds were recorded in the region of 4000-400 cm -1 by using KBr pallet on FT-IR Perkin spectro-photometer. H 1 NMR spectra were recorded on a DRX-300 Bruker FT-NMR spectrophotometer in DMSO-d 6 . The values of chemical shift are expressed in δ ppm as a unit. ...
Preprint
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Silica (SiO 2) catalyzed one-pot synthesis of 4-[(dialkylamino)methyl]-1,7-diphenylhepta-1,6-diene-3,5-dione. An expeditious synthesis under microwave irradiation method for curcumin Mannich base derivatives are known for its biological activity. Curcumin is naturally occurring yellow pigments isolated from Curcuma longa, structurally it is polyphenolic compounds consisting spectacular biological activity. Curcumin is also known as 'Indian Saffron', cultivated in most part of India. Curcumin traditionally recognized for its medicinal property in several Asian countries like 'India' and 'China'. However, clinical utility of curcumin is limited due to its poor bioavailability. Present methodology offers silica catalyzed one pot, productive technique to obtain curcumin Mannich base. Both, conventional and microwave irradiation methods were found productive. An eco-friendly catalyst as non-toxic, non-hazardous easily available used for the synthesis of curcumin analogue under conventional and microwave irradiation method. An expeditious reaction carried out under the microwave method with good to better yield. The final products were characterized by 1 H NMR.
... It further causes concentration-dependent suppression of IL-6 and IL-8 [184]. Few studies have also indicated that curcumin causes amelioration of the AKT pathway in inhibiting other types of tumors [185][186][187]. Some studies also reported that curcumins act through PTK2 and CaMKK2-mediated signaling pathways in cancer prevention [188]. ...
... They observed that curcumin suppressed proliferation and inhibition of NF-κB at in vitro level. Curcumin-mediated inhibition of NF-κB is associated with inhibition of IκB kinase activity, thereby preventing translocation of NF-κB into the nucleus [185,368]. ...
... NF-ĸB, NLRP3, cyclooxygenase-2 (COX-2), TNF-α, metalloproteinase-9 (MMP-9), MAPK/ERK, signal transducer and activator of transcription-3 (STAT3-transcription factors) and interleukins pathways. [140][141][142][143][144] It acts as a potential anti-inflammatory candidate against numerous conditions i.e. neurodegenerative disorders, cardiovascular complications, pulmonary oedema, metabolic syndrome, autoimmune and also for neoplastic diseases. [143] Presently, anti-inflammatory properties of curcumin are well studied and globally accepted and suppresses inflammation through multiple pathways. ...
... [143] Majorly, antiinflammatory activity of the curcumin is due to pro-inflammatory transcription factor NF-κB and also via IκB kinase signaling pathway. [142,145] Curcumin inhibits IL-6 and TNF-α expression also at both RNA and protein levels. [146] Interestingly, it is clearly demonstrated that curcumin inhibits the release of inflammasome NLRP3. ...
Article
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Pandemic coronavirus disease-2019 (COVID-19) is an infectious disease caused by the newly discovered virus “Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2)”. Considering the present scenario of COVID-19 outbreak and its impact on humankind, holistic remedies with respect to herbal medicine validated from ethnopharmacological rationale are now targeting approaches globally as a preventive care against SARS-CoV-2. Aim: This review is primarily focused on to deliver a concise fact of the coronaviridae family, pathophysiology, mechanism of action, ethnopharmacological validated Indian herbs for inhibiting the virus with possible targets. Experimental procedure: In this study, science mapping tool Bibliometrix R-package was used to perform bibliometric analysis and building data matrices for keywords co-occurrence investigation, country-wise scientific production; collaboration between the countries worldwide, co-word analysis on topic “keywords associated with SARS-CoV-2 and medicinal plants”. Results and Conclusion: Our findings is to deliver a concise knowledge about the coronaviridae family, pathophysiology, possible targets for managing the SARS-CoV-2, in addition to potential medicinal plants and their phytoconstituents against COVID-19. Target-specific inflammatory pathways due to post infection of SARS e.g. NLRP3, p38-MAPK, Metallopeptidase Domain 17; endocytosis pathways e.g. Clathrin, HMGB1 pathways are primarily highlighted along with relevant interleukins and cytokines, which directly/indirectly triggering to immune system and play a significant role. Based on selective pathways and potential lead, the outcome of our elaborated study put forward selected Indian medicinal plants that hold a very high probability as preventive care in this global crisis.
... NF-ĸB, NLRP3, cyclooxygenase-2 (COX-2), TNF-α, metalloproteinase-9 (MMP-9), MAPK/ERK, signal transducer and activator of transcription-3 (STAT3-transcription factors) and interleukins pathways. [140][141][142][143][144] It acts as a potential anti-inflammatory candidate against numerous conditions i.e. neurodegenerative disorders, cardiovascular complications, pulmonary oedema, metabolic syndrome, autoimmune and also for neoplastic diseases. [143] Presently, anti-inflammatory properties of curcumin are well studied and globally accepted and suppresses inflammation through multiple pathways. ...
... [143] Majorly, antiinflammatory activity of the curcumin is due to pro-inflammatory transcription factor NF-κB and also via IκB kinase signaling pathway. [142,145] Curcumin inhibits IL-6 and TNF-α expression also at both RNA and protein levels. [146] Interestingly, it is clearly demonstrated that curcumin inhibits the release of inflammasome NLRP3. ...
Article
Full-text available
This article is primarily reviewed and delivered a concise fact of the coronaviridae family, pathophysiology, mechanism of action, ethnopharmacological validated Indian herbs for inhibiting the virus with possible targets. Science mapping tool Bibliometrix R-package was used to understand bibliometric analysis on keywords associated with SARS-CoV-2 and medicinal plants. The outcome of our elaborated study put forward that the number of medicinal plants such as Andrographis paniculata, Azadirachta indica, Curcuma longa, Glycyrrhiza glabra, Ocimum sanactum, Tinospora cordifolia and Withania somnifera etc and their derivative phytoconstituents act on various pathways e.g. NLRP3, p38-MAPK, Metallopeptidase Domain 17; endocytosis pathways, HMGB1 triggers immune system directly/ indirectly against SARS-CoV-2/COVID-19 and could be the potential candidates as preventive remedies.
... CUR, as a chemotherapeutic agent, stands out due to its immense anti-neoplastic and anti-inflammatory effects. 19,20 In addition, it can function as a radiosensitizer and enhance the efficacy of RT by arresting tumor cells at the G2/M phase, making them more susceptible to radiation-induced damage. 21,22 Since most RT toxicities have an inflammatory nature, CUR's anti-inflammatory potential can be effective in significantly reducing them; 23 clinical evidence suggests that the adverse effects of RT are exceedingly low in CUR use. ...
... It has been reported that CUR may induce antiproliferative and proapoptotic effects on tumors associated with inhibition of signaling proteins, including transcription factors NF-kb, as well as tumor necrosis factors like TNF-a, cyclooxygenase 2, nitric oxide synthase, matrix metalloproteinase-9, urinary plasminogen activator, chemokines, cell surface adhesion molecules, cyclin D1 and growth factor receptors. 19 Accordingly, the CUR release profile suggests that Fe 3 O 4 -Au-BSA-FA-CUR can be considered as a highly attractive tool for achieving efficient synergistic RT. ...
Article
The development of highly integrated multifunctional nanomaterials with a superadditive therapeutic effect and good safety is an urgent but challenging task in cancer therapy research. The present study aims to design a nanoplatform that offers the opportunity to enhance antitumor activity while minimizing side effects. Given the Au-mediated X-ray radiation enhancement and the ability of Fe-based nanomaterials to create reactive oxygen species (ROS) and DNA damage, we anticipated that bimetallic Fe3O4-Au heterodimer would bring strong radiosensitizing capacity. Fe3O4-Au heterodimer surface was covered with bovine serum albumin (BSA) to achieve good surface functionality, stability and prolonged blood circulation. Folic acid (FA) moieties were added to the nanoformulation to increase tumor-homing, specificity and uptake. Finally, curcumin (CUR) was incorporated into the nanoparticle to function as a natural anticancer agent. The integration of all these components has yielded a single nanoplatform, Fe3O4-Au-BSA-FA-CUR, capable of successfully fulfilling the mission of superadditive cancer therapy to avoid the risks of organ removal surgery. The efficacy of the proposed nanoplatform was investigated in vitro and in vivo. High radiosensitizing ability, X-ray-induced ROS generation and DNA damage, and good biocompatibility were demonstrated through in vitro experiments. Also, the administration of Fe3O4-Au-BSA-FA-CUR with X-ray irradiation completely eradicated the tumor without any mortality and toxicity in healthy tissues in vivo. Our results highlight the potential of CUR-loaded Fe3O4-Au-BSA-FA heteronanostructure to enable synergistic localized radiochemotherapy and open up a new door to attractive possibilities that warrant further exploration.
... It further causes concentration-dependent suppression of IL-6 and IL-8 [184]. Few studies have also indicated that curcumin causes amelioration of the AKT pathway in inhibiting other types of tumors [185][186][187]. Some studies also reported that curcumins act through PTK2 and CaMKK2-mediated signaling pathways in cancer prevention [188]. ...
... They observed that curcumin suppressed proliferation and inhibition of NF-κB at in vitro level. Curcumin-mediated inhibition of NF-κB is associated with inhibition of IκB kinase activity, thereby preventing translocation of NF-κB into the nucleus [185,368]. ...
Article
Curcuma longa has been mentioned in Indian system of medicine for the management of wide range of diseases. C. longa and its metabolites like curcumin, ar-turmerone, methyl-curcumin, demethoxy-curcumin, bisdemethoxy-curcumin have also been reported beneficial in various types of cancer. Curcumin elicits anticancer properties chiefly by triggering apoptotic pathways in cancer cells. The properties are facilitated through diverse signaling pathways viz. pathways mediated by NF-kB, WNT/β-catenin pathway COX-2, LOX, STAT3, prostaglandin E2, phosphorylase kinase, VEGF, AKT, AP1, STAT3, PI3K, Akt, mTOR, ERK5, AP-1, TGF-b, PPARc, EBPa, NLRP3 inflammasome, p38MAPK, Nrf2, Notch-1, AMPK, TLR-4 etc. Present article highlights curcumin biosynthesis, phytochemistry and diverse molecular pathways involved to regulate several types of secondary messengers to exhibit anticancer activity in almost all the forms of cancer.
... Plant-derived low toxic phenolic compounds are known to exhibit anti-cancer activity by inducing apoptosis in cancer cells [27,40,41]. Curcumin is one such example which exhibits anticancer activity against various cancer types [42][43][44][45][46][47]. Curcumin has been replaced by more potent and bioavailable derivatives, which have attracted attention for the development of novel drugs [48]. ...
... Two-way ANOVA was conducted using Graph pad prism 7 tool and the p value was calculated between control and compound treated groups, where,*: p value < 0.05, **: p value < 0.005, ***: p value < 0.0001, ****: p value < 0.00001 1,2-bis[(3E,5E)-3,5-dibenzylidene-4-oxo-1-piperidyl]ethane-1,2-dione, by adding strong electronwithdrawing groups such as NO 2 and Cl-respectively to the backbone, has enhanced the anti-proliferative effect on the cancer cells particularly on ovarian cells (PA1) with stem cell-like properties. The cytotoxicity assays performed showed inhibition of cell growth by ST03 and ST08 in the range of 30-125 nM in both adherent and non-adherent cell lines which is~100 fold better than the parent compound curcumin, which was effective in the range of~10-100 μM on most of the cancer cells lines reported till date [43,44,50]. ST03 and ST08 are stable and bioavailable better than Curcumin (data not shown). ...
Article
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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.
... The anti-inflammatory effects of curcumin were mostly mediated through the regulation of the pro-inflammatory transcription factor, NF-κB. Curcumin has been shown to suppress the NF-κB pathway, specifically by inhibiting the activity of IκB kinase signalling [9]. Other inflammatory mediators affected by curcumin include the inhibition of signal transducers and activators of transcription (specifically STAT-3) expression, the inhibition of cyclooxygenase-2 (COX-2) [10], tumor necrosis factor alpha (TNFα), and interleukins [11]. ...
... As yet, the molecular mechanism by which this occurs is unknown, but a proposed mechanism suggests that it may be structural in nature; EF31 may partially bind to the ATP binding site of IKKβ, thus blocking the phosphorylation of Iκβ. Studies performed with related enones also exhibit inhibition of TNFα-induced activation of NF-κB that may occur at the level of the kinase complex [9,60]. ...
Article
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While curcumin has a range of therapeutic benefits, its potent anticancer activity remains an attractive avenue for anticancer research owing to the multifactorial nature of cancer itself. The structure of curcumin has thus been used as a lead to design more potent analogues, and diarylpentanoids in particular have shown improved cytotoxicity over curcumin. Investigations of diarylpentanoids have demonstrated that these compounds exert anti-cancer effects through several signalling pathways that are associated with cancer. This review focuses on selected diarylpentanoids and highlights molecular targets that modulate key pathways involved in cancer such as NF-κB, MAPK/ERK, and STAT signalling. Future research will need to focus on drug interactions to explore potential synergistic actions of diarylpentanoids and further establish the use of diverse animal models.
... In burns, it has been reported to inhibit the activity of phosphorylase kinase and subsequently the NF-KB/TGF- signalling pathways, thus, promote healing while simultaneously preventing scarring. In malignancy, active component of curcumin inhibits the activity of NF-KB and leads to apoptosis in basal carcinoma and melanoma cells in humans and is also known to cause upregulation of p53 (Jee et al. 1998;Marín et al. 2007;Siwak et al. 2005). This inhibition of NF-KB also helps in reducing the growth and proliferation of squamous cell carcinoma (Aggarwal et al. 2004). ...
Chapter
Skin conditions causing discomfort are of common occurrence. Dermatology is a branch of western medicine dedicated to the study of skin complications which is complimented with medicine to provide symptomatic treatment. These skin disorders have also been mentioned in Ayurveda as the disease of 'Kustha' which is caused by the imbalances in tridoshas and dhatus (bodily elements). Ayurvedic texts describe the use of plant derived polyherbal medicines and other products of common use in an Indian kitchen with potential to provide relief and treat a variety of skin conditions. Despite their diverse uses, they are known to impart adverse effects and interfere with the metabolome of the cells. This chapter outlines different skin conditions and an integrated approach of western and Ayurvedic medicines to treat them, some plant derived products of common usage and their associated side effects.
... These therapeutic properties include anti-inflammatory, antioxidant, immunomodulatory, antimicrobial, anti-ischemic, anti-cancer, and antirheumatic activities (Sahebkar, 2010(Sahebkar, , 2013Mirzaei et al., 2016;Momtazi et al., 2016;Pulido-Moran et al., 2016;Kunnumakkara et al., 2017). Curcumin can induce endoplasmic reticulum stress in SKCM by inhibiting classic signaling pathways, which included nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), Akt/Mtor, and Wnt/β-catenin, the expression of reactive oxygen species (ROS)thus the enhancement of oxidative stress injury has been increased (Bakhshi et al., 2008;Liao et al., 2017;Siwak et al., 2005;Zhang et al., 2015;Zheng et al., 2004). However, no systematic study on the mechanism, target, and effect of curcumin in the course of SKCM has been published thus far. ...
Article
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Objective: To reveal the potential mechanisms of curcumin for the treatment of skin cutaneous melanoma (SKCM) and its identify novel prognostic biomarkers. Methods: We searched the Cancer Genome Atlas and Traditional Chinese Medicine Systems Pharmacology database for the data on SKCM and curcumin. We conducted data analysis using R and online tools. The propagation and migration of SKCM cells were assessed with CCK-8 and scratch wound assays, respectively. We assessed apoptosis by TUNEL assay and western blot. Results: The survival analysis revealed that the mRNA expressions of DPYD , DPYS , LYN , PRKCQ, and TLR1 were significantly related to a favorable overall survival in SKCM patients. Additionally, the mRNA expression level of DPYD was associated with GPI , LYN , PCSK9 , PRKCQ, and TLR1 mRNAs. GSEA results showed that the prognostic hub genes were augmented with ultraviolet, apoptosis, and metastasis. Curcumin expressed proliferation and migration of SK-MEL-1 cells ( p < 0.05), and induced apoptosis ( p < 0.05) significantly. Conclusion: Curcumin may have potential therapeutic effects in SKCM by inhibiting cell proliferation and migration and inducing apoptosis by regulating oxygen-related signaling pathways. The hub genes might be identified as novel biomarkers for SKCM.
... Most curcumin supplements contain varying proportions of the three primary curcuminoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Preclinical data provide evidence of curcumin's antineoplastic properties. [1][2][3][4][5] For example, in colorectal cancer cell lines, curcumin, via caspase 3 activation leads to the disruption of APC/B-Catenin complex and down regulation of c-myc expression. 6 In vivo data also support a tumor suppressive effect in rodent models of cancer. ...
Article
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Curcumin inhibits UDP‐glucoronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this Phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, 4 grams) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200mg/m2 of IV infusion irinotecan on days 1 and 15 of a 28‐day cycle, to determine the maximum tolerated dose of PC. Thirteen participants received 4g of PC (maximum dose administered) to assess the effect on the pharmacokinetic properties of irinotecan and its metabolites, SN‐38 and SN‐38G. Irinotecan, SN‐38, and SN‐38G exposure equivalence with and without curcumin was assessed using AUC0‐6h. Safety assessments and disease response were also evaluated. The combination of irinotecan and PC was well tolerated. Since there was no dose limiting toxicity, the maximum dose administered (4g) was defined as the recommended phase 2 dose of PC. PC did not significantly alter the plasma exposure and other PK properties of irinotecan and its metabolites. There was no apparent increase in the incidence of irinotecan‐associated toxicities. The objective response rate was 3/19 (22%, 95% CI: 5 ‐ 39%), median progression free survival and overall survival (n=23) were 4 months (95% CI: 2.9 – 8.9 months) and 8.4 months (95% CI: 3.7 ‐ NE) respectively. Future studies are required to evaluate the efficacy of this combination.
... It was reported that curcumin may inhibit cell growth and proliferation in breast, colorectal [45][46][47][48], lung [49] and prostate cancer [50,51]. In melanoma cell lines incubated with curcumin extract, an inhibition of cell proliferation and increased level of apoptosis was associated with downregulation of NF-κB activity [52,53]. Another transcription factor, STAT3 (Figures 2 and 3), is overexpressed in many cancers. ...
Article
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Cancer is the second leading cause of death in humans. Despite rapid developments in diagnostic methods and therapies, metastasis and resistance to administrated drugs are the main obstacles to successful treatment. Therefore, the main challenge should be the diagnosis and design of optimal therapeutic strategies for patients to increase their chances of responding positively to treatment and increase their life expectancy. In many types of cancer, a deregulation of multiple pathways has been found. This includes disturbances in cellular metabolism, cell cycle, apoptosis, angiogenesis, or epigenetic modifications. Additionally, signals received from the microenvironment may significantly contribute to cancer development. Chemical agents obtained from natural sources seem to be very attractive alternatives to synthetic compounds. They can exhibit similar anti-cancer potential, usually with reduced side effects. It was reported that natural compounds obtained from fruits and vegetables, e.g., polyphenols, flavonoids, stilbenes, carotenoids and acetogenins, might be effective against cancer cells in vitro and in vivo. Several published results indicate the activity of natural compounds on protein expression by its influence on transcription factors. They could also be involved in alterations in cellular response, cell signaling and epigenetic modifications. Such natural components could be used in our diet for anti-cancer protection. In this review, the activities of natural compounds, including anti-cancer properties, are described. The influence of natural agents on cancer cell metabolism, proliferation, signal transduction and epigenetic modifications is highlighted.
... Curcumin antiproliferative effects were also observed in other three melanoma cell lines (C32, G-361, and WM 266-4), all of which are characterized by B-Raf mutations. In these cells, curcumin antitumor effects were associated with the suppression of NF-kB and IKK activity but were independent from the inhibition of B-Raf/MEK/ERK and Akt pathways [73]. ...
Article
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Curcumin, a main bioactive component of the Curcuma longa L. rhizome, is a phenolic compound that exerts a wide range of beneficial effects, acting as an antimicrobial, antioxidant, anti-inflammatory and anticancer agent. This review summarizes recent data on curcumin’s ability to interfere with the multiple cell signaling pathways involved in cell cycle regulation, apoptosis and the migration of several cancer cell types. However, although curcumin displays anticancer potential, its clinical application is limited by its low absorption, rapid metabolism and poor bioavailability. To overcome these limitations, several curcumin-based derivatives/analogues and different drug delivery approaches have been developed. Here, we also report the anticancer mechanisms and pharmacokinetic characteristics of some derivatives/analogues and the delivery systems used. These strategies, although encouraging, require additional in vivo studies to support curcumin clinical applications.
... Turmeric is a polyphenol derivative of Curcuma longa plant. Curcumin (diferuloylmethane) chief component of turmeric is a carotenoid pigment which has been used extensively in ayurvedic medicine for centuries, as it is nontoxic and has a anti-oxidant, analgesic, anti-inflammatory, antiproliferative, anti-angiogenesis, apoptosis inducing & antiseptic activities [7][8][9][10] . ...
Article
Background: Aspergillus flavous in betel nut secretes aflatoxin i.e. mycotoxin & tobacco which leads to production of free radicals and reactive oxygen species, thus increasing lipid peroxidation. Biological parameter of Lipid peroxidation is malondialdehyde. Hence present study was conducted to evaluate effect of turmeric on increased lipid peroxidation by using serum malondialdehyde levels & as a surrogate outcome on clinical signs & symptoms of oral submucous fibrosis (OSMF). Methods: In this study 270 subjects of which 30 were suffering from OSMF on turmeric with counseling them about stoppage of habit (group A), 30 subjects suffering from OSMF on turmeric without counseling them about stoppage of habit (group B), 30 subjects suffering from OSMF counseled for stoppage of habit but without turmeric medication (group C), 90 cases which were betel-nut habitual without OSMF (group D), 90 cases healthy control group (group E). Results: Statistically significant reduction in Serum MDA levels post treatment group A patients as compared to group B & group C (p<0.05). Mean difference was observed as 9.00 in group A, 3.81 in group B, 2.62 in group C. Conclusion: Increased serum MDA in OSMF can be used as an important marker in early diagnosis, treatment, prognosis and for prevention and clinical intervention of the disease. The antioxidant properties of turmeric reduce the oxidative stress even with effects of areca alkaloids. Serum MDA level was decreased in subjects taking turmeric medication for the period of 4 weeks
... Curcumin (diferuloylmethane), is a yellowish polyphenol derived from the turmeric plant Curcuma longa (62). In terms of mechanism of action, it acts on multiple molecular targets involved in melanoma pathogenesis such as Mek/Erk and PI3K/Akt (44), Erk/Akt (12), protein p53, Bcl-2 (29) and NF-kB (72). Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is naturally extracted from grapes, blueberries, cranberries, and peanuts. ...
Article
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Polyphenols such as curcumin (Cur) and resveratrol (Res) have been recently shown to have potential to inhibit proliferation of highly aggressive melanoma cells. This study was designed to investigate the feasibility of a topical delivery system, using a solid lipid nanoparticles (SLNs) loaded delivery systems, that can enhance the skin penetration and anti-cancer efficacy of combination of these polyphenols. Negatively charged Cur-Res SLNs with a mean diameter of 180.2 ± 7.7 nm were prepared using high shear homogenization method. Cur-Res SLNs were found to be stable up to 2 weeks under 4°C. The in vitro release study showed that Res was released five time more than curcumin. The permeability of resveratrol was about 1.67 times that of curcumin from the SLN-gel formulation which was significantly (p < 0.05) lower than from SLN suspension. More than 70% of Cur-Res SLNs were bound to skin locally in a skin binding study suggesting potentially utility of Cur-Res SLNs in the treatment of localized melanoma. In fact, the electrical cell-substrate impedance sensing (ECIS) measurements suggested that Cur-Res combination has potential to stop cell migration of B16F10 melanoma cells. Furthermore, both, Cur-Res SLNs and Cur-Res solution at the ratio of 3:1 demonstrated a strong synergistic inhibition of SK-MEL-28 melanoma cell proliferation. Further evaluation of Cur-Res SLNs in vivo melanoma models are warranted to establish the clinical utility of Cur-Res formulations in melanoma therapy. Graphical abstract
... It was reported that AKT-independent mechanism is involved in the inhibition of IKK [37]. In HNSCCs and melanoma, curcumin worked through AKT-independent mechanism [92] and epidermal growth factor receptor (EGFR) stimulated the AKT signaling cascade ultimately activate the NF-κB [93]. In a wide range of head and neck cancers EGFR overexpressed and standard platinum-based chemotherapy targeted the he EGFR/AKT signaling cascade to treat cancers [94] and it was reported that expression levels of multiple genes products like IL-6, IL-8, MMP-9, COX-2, CCL2 and Bcl-XL reduced regulated by NF-κB [60,91,[95][96][97]. ...
Article
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Medicinal plants are being used for therapeutic purposes since the dawn of human civilization. The therapeutic efficacy of medicinal plants is due to the presence of wide range phytochemical constituents or secondary metabolites. The medicinal plants are traditionally used for several types of ailments. Even in those pathological conditions where other methods of treatment fail to work. Curcuma longa Linn is very common ingredient used as spice in foods as preservative and coloring material in different part of the world. It has been used as a home remedy for a variety of diseases. Curcuma longa and its isolated constituent curcumin are widely evaluated for anticancer activity. Curcumin possesses broad remedial potential due to its multi-targeting effect against many different carcinoma including leukemia, genitourinary cancers, gastrointestinal cancers and breast cancer etc. Hence, Curcumin has potential for the development of new medicine for the treatment of several diseases.
... [73] The usual treatment was palliative (moderate dysplasia turning to milder dysplasia) was observed on using curcumin with no associated allergy and untoward effects. Curcumin can be tolerated to a dose as high as 2g/day without any side effect in the latest report by Siwak DR et al and Law CD et al. [74,75] Turmeric-suppresses tumor promoter-induced activation of transcription factor NF-Kβ and AP-1. [76] It also exerts anti-precancerous effects of Vitamin C and E and prevent lipid peroxidation and DNA damage. ...
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The use of herbal agents in medicine and dentistry is gaining importance worldwide. One such nutraceutical is turmeric which has come all the way from kitchen to clinic. Historically, turmeric finds a place in ancient Ayurvedic, Sidhha, Unani and Chinese systems of medicine. Although they are very popular in their day-today use, only few medicinal herbs have been scientifically evaluated for their potential in medical treatment. Several components, more than 100, have been isolated from turmeric. Curcumin, the principal curcuminoid, comprises of approximately 2-5% of turmeric. Curcumin is a natural polyphenolic product derived from turmeric which exhibits therapeutic activity mainly due to its chemical structure and unique physical and biological properties. Curcumin was first isolated in 1815and its chemical structure was determined in 1973. Chemically, it is a diferuloyl methane molecule [1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3,5-dione)] containing two ferulic acid residues joined by a methylene bridge. As a natural product, it is nontoxic and has little or no adverse effects. Safety evaluation of curcumin reveals that when curcumin was given to Wistar rats, guinea pigs and monkeys of both sexes at a dose of 300 mg/kg body weight, no pathological, behavioral abnormalities or lethality was observed. No adverse effects were observed on both growth and the level of erythrocytes, leucocytes, blood constituents such as haemoglobin, total serum protein, alkaline phosphatase, etc. Human clinical trials also indicate that curcumin has no toxicity when administered at doses of 1-8 g/day140and 10 g/day. Curcumin is not only responsible for the yellow color of turmeric but accounts for most of its pharmacological effects. It exhibits a big promise as a therapeutic agent due to its properties like antioxidant, analgesic, anti-inflammatory, antiseptic activity, anticarcinogenic activity, chemopreventive, Varun et al. World Journal of Pharmaceutical Research chemotherapeutic activity, anti-tumour, antiviral, antibacterial, and antifungal and is currently in human trials for a variety of conditions. The applications of curcumin in dentistry include its use as pit and fissure sealant, dental plaque detection system, subgingival irrigant and intracanal medicament. The antioxidant, anti-carcinogenic and anti-inflammatory properties of curcumin makes it appropriate to explore the role of curcumin in oral potentially malignant disorders (OPMD). OPMD represent a family of morphological alteration amongst which some may have an increased potential for malignant transformation. Potentially malignant disorders of the oral mucosa are also indicators of risk of likely future malignancies elsewhere in (clinically normal appearing) oral mucosa and not only sites specific predictors. In this review use of curcumin in OPMD like oral submucous fibrosis (OSMF), oral leukoplakia, oral lichen planus (OLP) and lesion associated with reverse smoking will be discussed. Various formulations of curcumin, its dosage, duration of therapy, outcomes used for reporting its efficacy and safety, adverse effects, and follow up will be analyzed for each of these conditions and presented. The mechanism of action of curcumin in OPMD will be elaborated. The intended audience/readership are the researchers working in the field of pharmacology, pharmaceutical industry and pharmacotherapy. It will equally benefit the clinicians dealing with OPMD as this chapter intends to synthesize the current data on use of curcumin in OPMD and suggest evidence-based future recommendations. Additionally, researchers in the field of oncology and cancer research are potential audience for this chapter.
... Several studies report anticancer activity of curcumin by modulating proteins such as cyclooxygenase-2 (COX-2), NF-κB and regulation of TNFα [5][6][7] inhibition of interleukins (IL-1, IL-6), cyclin dependent kinases (Cdk 1, Cdk 2, and Cdk 4) and Rb phosphorylation [8,9], TGF-β suppression and metalloproteinases [10]. Curcumin has proven to induce apoptosis in Melanoma cells [11], inhibits IKK/NF-κB transcription and increases P27 and P21 expression in lung cancer [12], acts on cyclin D1 activity regulation [13], on the stabilization of VEGF levels, restoration of proteins like Claudine 4 under hypoxia conditions [14] and increased apoptosis by activation of Caspase 8 and 3 [15][16][17]. ...
Article
Background Cancer is one of the main causes of death by disease; several alternative treatments have been developed to counteract this condition. Curcumin (diferuloylmethane), extracted from the rhizome of Curcuma longa, has antioxidant, antiinflammatory, and anti-cancer properties; however, it has low water solubility and poor intestinal absorption. Carrier systems, such as nanoemulsions, can increase the bioavailability of lipophilic bioactive compounds. Objective To evaluate the effect of curcumin nanoemulsions prepared with lecithin modified with medium-chain fatty acids as an emulsifier, on the expression of the Cdk4, Ccne2, Casp8 and Cldn4 genes involved in the carcinogenesis process in K14E6 transgenic mice. Methods The emulsifier was prepared by interesterification of medium-chain fatty acids, pure lecithin, and immobilized phospholipase-1 on Duolite A568. An Ultraturrax homogenizer and a Branson Ultrasonic processor were used for the preparation of nano-emulsions, and a Zetasizer evaluated the particle size. qRT-PCR analysis was performed to quantify the cancer-related genes expressed in the K14E6 mice. The development and evolution of skin carcinogenesis were assessed through histological analysis to compare cell morphology. Results Ca. 59% of the MCFA were incorporated via esterification into the PC within 12 hours of the reaction. An emulsifier yield used to formulate the NE of 86% was achieved. Nanoemulsions with a particle size of 44 nm were obtained. The curcumin nano-emulsion group had a 91.81% decrease in the tumorigenesis index and a reduction in tumor area of 89.95% compared to the sick group. Histological analysis showed that the group administered with free curcumin developed a microinvasive squamous cell carcinoma, as opposed to the group with nanoemulsion which presented only a slight inflammation. In gene expression, only a significant difference in Cdk4 was observed in the nanoemulsion group.
... 15 Numerous studies have shown that Cur induced its anticancer effect mainly through inhibition of nuclear factor-κB (NF-κB). 16 Also, Cur induced upregulations of some cellular proapoptotic molecules along with inhibition of many antiapoptotic molecules as cited in the comprehensive review article of Panda et al. 17 Another natural anticancer compound from a plant source is caffeine (Caff). Caff inhibits a variety of protein kinases including ataxia-telangiectasia-mutated (ATM)/ Rad3-related (ATR) kinases. ...
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Cellular senescence is a process of physiological growth arrest that can be induced by intrinsic or extrinsic stress signals. Some cancer therapies are associated with senescence of cancer cells with a typical cell cycle arrest. Doxorubicin (Dox) induces senescence by a p53-dependent pathway and telomere dysfunction of numerous cancers. However, cellular senescence induces suppression in proliferation activity, and these cells will remain metabolically active and play an important role in tumor relapse and development of drug resistance. In the current study, we investigated the apoptotic effect of curcumin (Cur), caffeine (Caff), and thymoquinone (TQ) on senescent colon cancer HCT116 and breast cancer MCF7 cell lines treated with Dox. Results showed typical senescence markers including decreased bromodeoxyuridine incorporation, increased accumulation of senescence-associated β-galactosidase (SA-β-gal), cell cycle arrest, and upregulation of p53, P-p53, and p21 proteins. Annexin-V analysis by flow cytometry revealed 2- to 6-fold increases in annexin-V–positive cells in Dox-treated MCF7 and HCT116 cells by Cur (15 µM), Caff (10 mM), and TQ (50 µM; P < .001). In comparison between proliferative and senescent of either HCT116 or MCF7 cells, Caff at 15 mM and TQ at 25 µM induced significant increases in apoptosis of Dox-treated cells compared with proliferative cells ( P < .001). Data revealed that Cur, Caff, and TQ potentially induced apoptosis of both proliferative and senescent HCT116 and MCF7 cells. In vivo and clinical trials are of great importance to validate this result.
... The compound curcumin (diferuloylmethane), which is the primary active constituent of turmeric, has been extensively studied for its anti-inflammatory activity in a variety of diseases in experimental and clinical studies [14]. Curcumin has been shown to exert anti-inflammatory actions by downregulating the activity of cyclooxygenase-2, lipoxygenase, and inducible nitric oxide synthase enzymes [15,16], inhibiting the production of pro-inflammatory cytokines (Tumor Necrosis Factor Alpha (TNF-α), Interleukin (IL)-1, -2, -6, -8 and -12, macrophage inflammatory protein (MIP), and monocyte chemoattractant protein-1 (MCP-1)) [17], and downregulating mitogen-activated and Janus kinases [18,19]. Anti-inflammatory activities are likely mediated by curcumin-mediated suppression of NFκB [16,17,20]. ...
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Herpes Simplex Virus Type 2 (HSV-2) is one of the most prevalent sexually transmitted viruses and is a known risk factor for HIV acquisition in the Female Genital Tract (FGT). Previously, we found that curcumin can block HSV-2 infection and abrogate the production of inflammatory cytokines and chemokines by genital epithelial cells in vitro. In this study, we investigated whether curcumin, encapsulated in nanoparticles and delivered by various in vivo routes, could minimize inflammation and prevent or reduce HSV-2 infection in the FGT. Female mice were pre-treated with curcumin nanoparticles through oral, intraperitoneal and intravaginal routes, and then exposed intravaginally to the tissue inflammation stimulant CpG-oligodeoxynucleotide (ODN). Local intravaginal delivery of curcumin nanoparticles, but not intraperitoneal or oral delivery, reduced CpG-mediated inflammatory histopathology and decreased production of pro-inflammatory cytokines Interleukin (IL)-6, Tumor Necrosis Factor Alpha (TNF-α) and Monocyte Chemoattractant Protein-1 (MCP-1) in the FGT. However, curcumin nanoparticles did not demonstrate anti-viral activity nor reduce tissue pathology when administered prior to intravaginal HSV-2 infection. In an alternative approach, intravaginal pre-treatment with crude curcumin or solid dispersion formulations of curcumin demonstrated increased survival and delayed pathology following HSV-2 infection. Our results suggest that curcumin nanoparticle delivery in the vaginal tract could reduce local tissue inflammation. The anti-inflammatory properties of curcumin delivered to the vaginal tract could potentially reduce the severity of HSV-2 infection and decrease the risk of HIV acquisition in the FGT of women.
... The antiproliferative role of curcumin is attributed by regulating transcription factors, including NF-κB and protein kinases in cell cycle. In a malignant cell line, curcumin has been studied to exhibit an antiproliferative potential by inhibiting the binding effect of NF-κB (15). Curcumin also exhibit the similar effects on AP-1, EGR, and B-catenin (16). ...
... Curcuminoids possess diverse biological properties, including anti-inflammatory [5], anticancer [6], antioxidant [7], antiproliferative [8], and antiangiogenic activities [9]. In addition, curcuminoids can affect the prevention and treatment of Alzheimer's disease [10,11]. ...
Article
Two hydroxybenzoyl amines, 4-hydroxybenzoyl tyramine (4-HBT) and N-2-hydroxybenzoyl tryptamine (2-HBT), were synthesized using Escherichia coli. While 4-HBT was reported to demonstrate anti-atherosclerotic activity, 2-HBT showed anticonvulsant and antinociceptive activities. We introduced genes (chorismate pyruvate-lyase (ubiC), tyrosine decarboxylase (TyDC), isochorismate synthase (entC), isochorismate pyruvate lyase (pchB), and tryptophan decarboxylase (TDC)) for each substrate, 4-hydroxybenzoic acid (4-HBA), tyramine, 2-hydroxybenzoic acid (2-HBA), and tryptamine, respectively, in E. coli. Genes for CoA ligase (hbad) and amide formation (CaSHT and OsHCT) were also introduced to form hydroxybenzoic acid and amine conjugates. In addition, we engineered E. coli to provide increased substrates. These approaches led to the yield of 259.3 mg/L 4-HBT and 227.2 mg/L 2-HBT could be applied to synthesize diverse bioactive hydroxybenzoyl amine conjugates.
... In some tumors, AKT signaling pathway is suppressed by curcumin e.g. malignant gliomas and pancreatic cancer, whereas in HNSCCs and melanoma, the role of curcumin is independent of AKT [107]. ...
... Curcumin is also potent against cancer types that are difficult to treat, like melanoma [7][8][9] or glioblastoma [10], as demonstrated by the work of Maiti et al. in this issue. They observed increased levels of autophagy and decreased levels of mitophagy markers, along with inhibition of the PI3K-Akt/mTOR pathway after treatment of glioblastoma cells with curcumin or solid lipid curcumin particles. ...
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The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, are a matter of public interest. An internet search of the term “Curcumin” displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a “miracle cure”. This circumstance makes it very difficult for researchers, whose work is scientifically sound and evidence is based on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin’s way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin’s molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future—either as monotherapy or in combination with other drugs or therapeutic applications.
... As regards its anti-melanoma effects, curcumin was shown to arrest cell proliferation and to trigger both extrinsic and intrinsic apoptosis in vitro and in vivo [148][149][150][151][152][153][154][155]. In particular, it was reported to inhibit the NF-κB [156][157][158], STAT3 [159], Akt/mTOR [160] and Wnt/β-catenin [44] signaling pathways, to induce ER stress [161], to activate mammalian Sterile 20-like kinase 1 (MST1)/JNK cascade [162] and to enhance ROS production [163,164] in melanoma cells. ...
Article
Melanoma is the most fatal form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, targeted therapy and immunotherapy. However, these treatment strategies are associated with development of drug resistance and severe side effects. In recent years, natural compounds have also been extensively studied for their anti-melanoma effects, including tumor growth inhibition, apoptosis induction, angiogenesis and metastasis suppression and cancer stem cell elimination. Moreover, a considerable number of studies reported the synergistic activity of phytochemicals and standard anti-melanoma agents, as well as the enhanced effectiveness of their synthetic derivatives and novel formulations. However, clinical data confirming these promising effects in patients are still scanty. This review emphasizes the anti-tumor mechanisms and potential application of the most studied natural products for melanoma prevention and treatment.
... This compound has anti-inflammatory, antitumoral, antioxidant, and cardioprotective activities and several other properties (75)(76)(77)(78)(79)(80)(81)(82). Curcumin can inhibit NF-kB activation through restriction of IkBa kinase and Akt activation (83)(84)(85)(86)(87)(88)(89). This change results in the inhibition of NF-kB-regulated gene products that control apoptosis, proliferation, invasion and angiogenesis (90,91). ...
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Objectives: Oxidative stress results from an imbalance between the generation and elimination of oxidant species. This condition may result in DNA, RNA and protein damage, leading to the accumulation of genetic alterations that can favor malignant transformation. Persistent infection with high-risk human papillomavirus types is associated with inflammatory responses and reactive oxygen species production. In this context, oxidative stress, chronic inflammation and high-risk human papillomavirus can act in a synergistic manner. To counteract the harmful effects of oxidant species, protective molecules, known as antioxidant defenses, are produced by cells to maintain redox homeostasis. In recent years, the use of natural antioxidants as therapeutic strategies for cancer treatment has attracted the attention of the scientific community. This review discusses specific molecules and mechanisms that can act against or together with oxidative stress, presenting alternatives for cervical cancer prevention and treatment.
... 31,32 Growing evidence also reveals that curcumin is able to influence many cellular and molecular signaling pathways involved in cancer pathogenesis such as JAK-2/STAT-3, Mcl-1, BCl-2, MST1, Foxo3, JNK, Bim-1, Bax and making it a promising therapeutic agent which can be employed against various cancers. 33,34 In a study, Zhang et al., assessed the therapeutic effects of curcumin on the many biological processes such as proliferation, migration and metastasis of human melanoma cells. 35 In our study, melanoma cells (A375 cell line) were treated with different doses of curcumin in vitro. ...
Article
Esophageal cancer is a common malignant tumor with an increasing trend during the past three decades. Currently, esophagectomy, often in combination with neoadjuvant chemo‐ and radiotherapy, is the cornerstone of curative treatment for esophageal cancer. However, esophagostomy is related to significant risks of perioperative mortality and morbidity, as well as lengthy recovery. Moreover, the adjuvant therapies including chemotherapy and radiotherapy are associated with numerous side effects, limiting compliance and outcome. The dietary agent curcumin has been extensively studied over the past few decades and is known to have many biological activities especially in regard to the prevention and potential treatment of cancer. This review summarizes the chemo‐preventive and chemotherapeutic potential of curcumin in esophageal cancer in both preclinical and clinical settings. This article is protected by copyright. All rights reserved.
... Among various pharmacological activities, curcumin had proved its credential as a vital source of chemopreventive agent against varieties of cancer. Curcumin has been studied in multiple human carcinomas including melanoma, head and neck, pancreatic, prostate, breast, colon, and ovarian cancers [7][8][9][10][11][12][13][14][15]. Many in vitro studies have been conducted on several cancer cell lines showing strong efficacy of curcumin against several human cancers. ...
Chapter
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Cancer has become one of the leading causes of death worldwide. Presently, available chemotherapeutic agents have several limitations including severe side effects. Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa. Curcumin has been used extensively as spice in many Asian countries and in Ayurvedic medicines. It is nontoxic and has shown to possess various medicinal properties including antioxidant, anti-inflammatory, and antibacterial. Recent investigations have shown that curcumin exerts anticancer properties in various cancer cell models and targets variety of biological pathways involved in cell cycle regulation, apoptosis, mutagenesis, angiogenesis, and metastasis. NF-κB, p53, Nrf2, NFAT, MMPs, STATs, and uPA are important molecular targets of curcumin in multiple cancer models. Enzymes involved in redox balance inside the cells including superoxide dismutases, catalase, and glutathione peroxidase are modulated by curcumin. However, bioavailability, water insolubility, short life span, and rapid systemic clearance of curcumin have posed limitations in developing curcumin as an effective chemotherapeutic agent. To address these challenges, curcumin has been used in combinations with many other chemotherapeutic drugs which have shown encouraging results. This chapter deals with the current information available for the cancer chemopreventive activities of curcumin in various in vitro and in vivo cancer models including epidemiological studies and human trials. Also, molecular pathways involved in the manifestation of biological activities of curcumin against various processes of cancer development have been discussed.
... Among various pharmacological activities, curcumin had proved its credential as a vital source of chemopreventive agent against varieties of cancer. Curcumin has been studied in multiple human carcinomas including melanoma, head and neck, pancreatic, prostate, breast, colon, and ovarian cancers [7][8][9][10][11][12][13][14][15]. Many in vitro studies have been conducted on several cancer cell lines showing strong efficacy of curcumin against several human cancers. ...
... The anticancer activities of curcumin are mentioned in various reports providing evidence that it can cause cell death in cancer cell lines and retard tumour growth in animal models. Curcumin is actively reported in the suppression of many cancers like breast, head and neck, colon, oral and prostate cancers (Hanif et al. 1997;Elattar and Virji 2000;Mukhopadhyay et al. 2001;Aggarwal et al. 2004;LoTempio et al. 2005;Siwak et al. 2005;Lin et al. 2007;Wang et al. 2008). ...
Chapter
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Cancer is an alarming disease and quite lethal in nature in developed and developing nations. Many new therapeutic agents and therapies are available in the market but have some severe side effects on human beings’ organs. These therapeutic agents are quite costly and not easily available in some of the developing nations. Various scientifc reports have shown that chemoprevention through naturally derived herbal and dietary phytochemicals is an innovative therapeutic tool against different cancer types. These herbal phytochemicals have shown their potential anticancer activity in both in vitro and in vivo studies. Further, many of them have been successfully proved for their chemopreventive property by inducing apoptosis equivalent to certain other chemical drugs without causing any side effects. The combinational role of herbal and dietary phytochemicals has proved to be very effective against cancer prevention. The present chapter summarised the effectiveness of herbal and dietary phytochemicals for chemoprevention and also highlighted their combinational role on various kinds of cancer. Keywords Anticancer · Therapeutic agents · Herbal phytochemicals ·
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Background: Curcumin, an active compound of turmeric spice is one of the most-studies natural compounds and have been widely recognized as chemopreventive agents. Several molecular mechanisms have been proven, curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as inhibition of carcinogenesis process. Objective: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. Methods: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed central and Google scholar for the implication of curcumin in cancer management along with special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com and www.freshpatents.com. Result: Recent studies based on cancer cells have proven that curcumin have potential effects against cancer cells, prevent the growth of cancer and act as cancer therapeutic agents. Besides, curcumin exerted anticancer effects through inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. Conclusion: Accumulating evidences suggest that curcumin has potentiality to inhibit cancer growth, induced apoptosis and modulate various cell signalling pathways molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy and safe dose in the management of various cancers.
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A structure activity relationship study of cyclocurcumin-derived, diaryl γ-dihydropyrone-based inhibitors of amyloid β aggregation is described. Optimization of the diaryl γ-dihydropyrone framework and two phenolic rings resulted in the identification of diaryl γ-dihydropyrone type cyclocurcumin analogue AY1511, which exhibited potent anti-amyloid β aggregation activity (leading to nanorod-like fragments), sufficient water solubility, and low cytotoxicity.
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Aims: In our study, the anticancer effects of a semisynthetic p-quinol, protoapigenone 1'-O-butyl ether (PABut), were tested in human melanoma A375 cells also in comparison with natural congener, protoapigenone (PA). Main methods: The cytotoxic effect of PABut and PA was determined using MTT assay. Flow cytometry analysis was used to evaluate the influence of the compounds tested on ROS generation and cell cycle distribution in A375 cells. Moreover, apoptosis was evaluated by AO/EB dual staining as well as by flow cytometry. Markers of senescence were quantified by spectrofluorimetry and by Western blot analysis. Key findings: Both PABut and PA showed significant cytotoxicity against melanoma A375 cells at sub-micromolar concentrations. Both protoflavones induced comparable cell cycle arrest in G2/M phase. However, a more profound upregulation of intracellular ROS levels was found following PABut treatment. An increased apoptosis in the cells following 48 h treatment with both protoflavones tested was also confirmed. Both compounds tested remarkably upregulated p21 protein levels in A375 cells. Unlike PA, PABut significantly decreased protein levels of NAD+-dependent deacetylase SirT1 and β-actin accompanied by mild significant upregulation of mitochondrial SOD2 and senescence markers, p16 protein and SA-β-Gal activity. However, a significant upregulation of p53 only following PA treatment was found. Significance: These results suggest that PABut and PA confer high chemotherapeutic potential in melanoma cells and are suitable for further testing. Furthermore, modification of protoapigenone with 1'-O-butyl ether moiety can be associated with improved senescence-inducing effect and, thus, enhanced chemotherapeutic potency of PABut compared to the unmodified natural protoflavone.
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Background Curcumin, a major active principle of Curcuma longa. There are more than 1700 citations in the Medline reflecting various biological effects of curcumin. Most of these biological activities are associated to the antioxidant, anti-inflammatory and antitumor activity of the molecule. Several reports suggest various targets of natural curcumin that includes growth factors, growth factor receptor, cytokines, enzymes and gene regulators of apoptosis. This review focuses on the improved curcumin derivatives that targets the cancer and inflammation. Methodology In this present review, we explored the anticancer drugs with curcumin-based drugs under pre-clinical and clinical studies with critical examination. Based on the strong scientific reports of patentable and non-patented literature survey, we have investigated the mode of the interactions of curcumin-based molecules with the target molecules. Results Advanced studies have added new dimensions of molecular response of cancer cells to curcumin at genomic level. However, poor bioavailability of the molecule seems to be the major limitation of the curcumin. Several researchers have involved to improve the curcumin derivatives to overcome this limitation. Sufficient data of clinical trials to various cancers that include multiple myeloma, pancreatic cancer and colon cancer are also discussed. Conclusion The detailed analysis of structure activity relationship (SAR) and common synthesis of curcumin-based derivatives are discussed in review. Utilising the predictions of in silico coupled with validation reports of in vitro and in vivo studies have concluded many targets for curcumin. Among them, cancer related inflammation genes regulating curcumin-based molecules are very promising target to overcome hurdle in the multimodality therapy of cancer.
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The development of near-infrared difluoroboron complexes of curcumin analogues to specifically detect one or both analytes in the solid state is highly desirable. Herein, three novel BF2-curcumin analogues with an extended π-conjugation (TBN, TBT and NBN) have been rationally designed and developed, in which the dimethylamino group acted as electron donator (D) and the proton-binding site, and the BF2bdk moiety not only functioned as electron acceptor (A) but also responded to amine vapors. And they exhibited excellent solvent-dependent photophysical properties in solutions and PMMA film state. Moreover, BF2-curcumin analogues TBN and NBN showed an unprecedented “dual-dual” sensing performance (the first dual: simultaneous response to both acid and amine vapors; the second dual: fluorescent turn-on sensing and colorimetric sensing) in solutions and PMMA film state. Therefore, they would be utilized as multifunctional sensing materials for specific detection towards volatile acid and amine vapors in environmental and biological systems.
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The advancements in the field of imaging and diagnostics have been benefitted by the concurrent expansion of molecular probes space to monitor the diverse biological targets and events. The misfolding and aggregation of amyloid β peptide as well as Tau protein generate toxic polymorphic species (referred to as alloforms in this article) which are formally designated as core AD biomarkers by National Institute on Aging and Alzheimer’s Association Research Framework (NIA-AA 2018). Positron emission tomography and magnetic resonance imaging, which are currently the efficient and sophisticated techniques in the clinical diagnosis, are incapable of detection and differentiation of various alloforms besides being not easily operable and affordable by the common people. As a consequence, fluorescence optical imaging has gained great impetus besides many recent technological advancements that have positioned its sensitivity at par with PET and MRI in addition to offering the possibility of alloform detection, rapid analyses and economic benefits to cater to a larger population. In addition, there exists an array of biomarkers or pathophysiological conditions that are known to aggravate the disease progression. This emphasises the importance of molecular tools and methods for the detection of various known as well as yet to be identified AD biomarkers. The molecular and hybrid tools intended for detection and imaging of biomarkers inside the AD brain must cross the blood brain barrier which is one of the persistent challenges for synthetic organic chemists and in this context various strategies are discussed. In this review, we have proposed multiplexed and multimodal analytical approach for the in vitro and in vivo detection and imaging of the core and indirect biomarkers in brain and bio-fluids such as cerebrospinal fluid (CSF) and blood among others to generate characteristic fingerprints to distinguish between healthy and AD patients with precision. Overall, this review offers critical discussions on design, properties, functions, advantages and limitations of the existing molecular probes besides providing current and future prospects for the development of novel diagnostic and theranostic tools for AD
Nature is a rich source of natural drug-like compounds with almost zero side effects. Phytochemicals better known as “Natural Products” are found abundantly in a number of plants. Since time immemorial, spices have been widely used in Indian cuisine as flavoring and colouring agents. Most of these spices and condiments are derived from various biodiversity hotspots in India (which contributes 75% of global spice production) and form the crux of India’s multidiverse and multicultural cuisine. Apart from their aroma, flavor and taste, these spices and condiments are known to possess several medicinal properties also. Most of these spices find considerable mention in Ayurveda, the indigenous system of medicine, as panaceas for several aliments. The antimicrobial, antioxidant, antiproliferative, antihypertensive and antidiabetic properties of several of these natural products are well documented in Ayurveda. These phytoconstituemts are known to act as functional immunoboosters, immunomodulators as well as anti-inflammatory agents. As anticancer agents, their mechanistic action involves cancer cell death via induction of apoptosis, necrosis and autophagy. The present review provides a comprehensive and collective update on the potential of 65 commonly used spices as well as their bioactive constituents as anticancer agents. The review also provides an in-depth update of all major in vitro, in vivo, clinical and pharmacological studies done on these spices with special emphasis on the potential of these spices and their bioactive constituents as potential functional foods for prevention, treatment and management of cancer.
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Raf-1 is a serine/threonine kinase which is essential in cell growth and differentiation. Tyrosine kinase oncogenes and receptors and p21ras can activate Raf-1, and recent studies have suggested that Raf-1 functions upstream of MEK (MAP/ERK kinase), which phosphorylates and activates ERK. To determine whether or not Raf-1 directly activates MEK, we developed an in vitro assay with purified recombinant proteins. Epitope-tagged versions of Raf-1 and MEK and kinase-inactive mutants of each protein were expressed in Sf9 cells, and ERK1 was purified as a glutathione S-transferase fusion protein from bacteria. Raf-1 purified from Sf9 cells which had been coinfected with v-src or v-ras was able to phosphorylate kinase-active and kinase-inactive MEK. A kinase-inactive version of Raf-1 purified from cells that had been coinfected with v-src or v-ras was not able to phosphorylate MEK. Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. We conclude that MEK is a direct substrate of Raf-1 and that the activation of MEK by Raf-1 is due to phosphorylation by Raf-1, which is sufficient for MEK activation. We also tested the ability of protein kinase C to activate Raf-1 and found that, although protein kinase C phosphorylation of Raf-1 was able to stimulate its autokinase activity, it did not stimulate its ability to phosphorylate MEK.
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AP-1 is a collection of dimeric sequence specific, DNA binding, transcriptional activators composed of Jun and Fos subunits. The composition, the level and the activity of AP-1 complexes are regulated in response to extracellular stimuli. An important role in this regulation is played by mitogen-activated protein kinases (MAPKs). The specific roles of three MAPKs, namely ERK, JNK and FRK, in modulation of both the level and activity of AP-1, are discussed.
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NF-kappaB activation in response to UV irradiation of HeLa cells or of primary human skin fibroblasts occurs with two overlapping kinetics but totally different mechanisms. Although both mechanisms involve induced dissociation of NF-kappaB from IkappaBalpha and degradation of IkappaBalpha, targeting for degradation and signaling are different. Early IkappaBalpha degradation at 30 min to approximately 6 h is not initiated by UV-induced DNA damage. It does not require IkappaB kinase (IKK), as shown by introduction of a dominant-negative kinase subunit, and does not depend on the presence of the phosphorylatable substrate, IkappaBalpha, carrying serines at positions 32 and 36. Induced IkappaBalpha degradation requires, however, intact N- (positions 1-36) and C-terminal (positions 277-287) sequences. IkappaB degradation and NF-kappaB activation at late time points, 15-20 h after UV irradiation, is mediated through DNA damage-induced cleavage of IL-1alpha precursor, release of IL-1alpha and autocrine/paracrine action of IL-1alpha. Late-induced IkappaBalpha requires the presence of Ser32 and Ser36. The late mechanism indicates the existence of signal transfer from photoproducts in the nucleus to the cytoplasm. The release of the 'alarmone' IL-1alpha may account for some of the systemic effects of sunlight exposure.
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Recent work has suggested a role for the serine/threonine kinase Akt and IκB kinases (IKKs) in nuclear factor (NF)-κB activation. In this study, the involvement of these components in NF-κB activation through a G protein-coupled pathway was examined using transfected HeLa cells that express the B2-type bradykinin (BK) receptor. The function of IKK2, and to a lesser extent, IKK1, was suggested by BK-induced activation of their kinase activities and by the ability of their dominant negative mutants to inhibit BK-induced NF-κB activation. BK-induced NF-κB activation and IKK2 activity were markedly inhibited by RGS3T, a regulator of G protein signaling that inhibits Gαq, and by two Gβγ scavengers. Co-expression of Gαq potentiated BK-induced NF-κB activation, whereas co-expression of either an activated Gαq(Q209L) or Gβ1γ2 induced IKK2 activity and NF-κB activation without BK stimulation. BK-induced NF-κB activation was partially blocked by LY294002 and by a dominant negative mutant of phosphoinositide 3-kinase (PI3K), suggesting that PI3K is a downstream effector of Gαq and Gβ1γ2 for NF-κB activation. Furthermore, BK could activate the PI3K downstream kinase Akt, whereas a catalytically inactive mutant of Akt inhibited BK-induced NF-κB activation. Taken together, these findings suggest that BK utilizes a signaling pathway that involves Gαq, Gβ1γ2, PI3K, Akt, and IKK for NF-κB activation.
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The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-kappaB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-kappaB has been controversial, with evidence supporting induction of nuclear translocation of NF-kappaB via activation of IkappaB kinase activity and/or the stimulation of the transcription function of NF-kappaB. Here we demonstrate that Akt targets the transactivation function of NF-kappaB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on IkappaB kinase beta activity and on the mitogen-activated protein kinase p38 (p38). Activation of RelA/p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-kappaB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-1beta to activate NF-kappaB is known to involve Akt, and we show here that IL-1beta induces p38 activity in manner dependent on Akt and IkappaB kinase activation. Interestingly, activated Akt and the transcriptional co-activators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through IkappaB kinase and p38, induces the transcription function of NF-kappaB by stimulating the RelA/p65 transactivation subunit of NF-kappaB.
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Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) is thought to serve as an oncogenic signaling pathway which can be activated by Ras. The role of PI3K/Akt in Ras-mediated transformation of intestinal epithelial cells is currently not clear. Here we demonstrate that inducible expression of oncogenic Ha-Ras results in activation of PKB/Akt in rat intestinal epithelial cells (RIE-iHa-Ras), which was blocked by treatment with inhibitors of PI3K activity. The PI3K inhibitor, LY-294002, partially reversed the morphological transformation induced by Ha-Ras and resulted in a modest stimulation of apoptosis. The most pronounced phenotypic alteration following inhibition of PI3K was induction of G(1) phase cell cycle arrest. LY-294002 blocked the Ha-Ras-induced expression of cyclin D1, cyclin-dependent kinase (CDK) 2, and increased the levels of p27(kip). Both LY-294002 and wortmannin significantly reduced anchorage-independent growth of RIE-iHa-Ras cells. Forced expression of both the constitutively active forms of Raf (DeltaRaf-22W or Raf BXB) and Akt (Akt-myr) resulted in transformation of RIE cells that was not achieved by transfection with either the Raf mutant construct or Akt-myr alone. These findings delineate an important role for PI3K/Akt in Ras-mediated transformation of intestinal epithelial cells.
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Constitutive IKK activity associated with increased IkappaBalpha phosphorylation and degradation contribute to the high level of endogenous nuclear factor-kappaB (NF-kappaB) activation in Hs294T melanoma cells as compared with RPE cells (R. L. Shattuck-Brandt and A. Richmond, Cancer Res., 57: 3032-3039, 1997; M. N. Devalaraja et al., Cancer Res., 59: 1372-1377, 1999). To determine whether this endogenous NF-kappaB activation was characteristic of melanoma, we examined the level of constitutive activation of NF-kappaB in a number of melanoma cell lines. We demonstrate here that eight melanoma cell lines exhibit increased IkappaB kinase (IKK) activity, enhanced phosphorylation of IkappaBalpha and p65, and enhanced nuclear localization of p65/p50 in comparison to normal human epidermal melanocytes. The chemokines, CXC ligand 1 (CXCL1) and CXCL8, but not CXCL5, are highly expressed in most of the melanoma cell lines, suggesting that the constitutive production of chemokines is highly correlated to endogenous NF-kappaB activity. Our failure to observe a direct relationship between the fold activation of IKK, CXCL1, or CXCL8 mRNA levels and secretion of these chemokines into the culture medium suggest that regulation of chemokine expression also occurs at the posttranscription level of mRNA stability and/or translational control. Moreover, recombinant CXCL1 can directly induce IKK activity in normal human epidermal melanocytes in a concentration-dependent manner after up-modulation of CXCL1 protein expression, whereas inhibition of IKKbeta activity results in down-modulation of CXCL1 protein expression. Finally, CXCL1 antibody blocks IKK activity and inhibits the proliferation of melanoma cells to further support the concept that the constitutive activation of NF-kappaB and autocrine effects of CXCL1 play an important role in the pathogenesis of melanoma.
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The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK)1 and ERK2, involved in regulating cell growth and differentiation, are constitutively active in A375 and WM239 human melanoma cells. Using PD098059, an inhibitor of MAPK kinase (MEK), we investigated the role of persistently activated ERK1/2 in cell growth. The inhibition of MAPK activity induced a dose-dependent growth arrest in G(0)/G(1) phase. Correspondingly, we observed the up-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27/Kip1 and hypophosphorylation of the retinoblastoma protein. Further studies showed that PD098059 treatment significantly decreased Cdk2 kinase activity, most probably owing to an augmented level of p27/Kip1 associated with cyclin E-Cdk2 complexes. The accumulation of p27/Kip1 protein in A375 cells was attributed to its increased stability. Our findings suggest that constitutively active ERK1/2 kinases contribute to the growth of melanoma cells by negative regulation of the p27/Kip1 inhibitor.
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Respiratory syncytial virus (RSV) infects airway epithelial cells, resulting in cell death and severe inflammation through the induction of NF-kappaB activity and inflammatory cytokine synthesis. Both NF-kappaB activity and apoptosis regulation have been linked to phosphatidylinositol 3-kinase (PI 3-K) and its downstream effector enzymes, AKT and GSK-3. This study evaluates the role of PI 3-K and its downstream mediators in apoptosis and inflammatory gene induction during RSV infection of airway epithelial cells. Whereas RSV infection alone did not produce significant cytotoxicity until 24-48 h following infection, simultaneous RSV infection and exposure to LY294002, a blocker of PI 3-K activity, resulted in cytotoxicity within 12 h. Furthermore, we found that RSV infection during PI 3-K blockade resulted in apoptosis by examining DNA fragmentation, DNA labeling by terminal dUTP nick-end labeling assay, and poly(ADP-ribose) polymerase cleavage by Western blotting. RSV infection produced an increase in the phosphorylation state of AKT, GSK-3, and the p85 regulatory subunit of PI 3-K. The activation of PI 3-K by RSV and its inhibition by LY294002 was confirmed in direct PI 3-K activity assays. Further evidence for the central role of a pathway involving PI 3-K and AKT in preserving cell viability during RSV infection was established by the observation that constitutively active AKT transfected into A549 cells prevented the cytotoxicity and apoptosis of combined RSV and LY294002 treatment. Finally, both PI 3-K inhibition by LY294002 and AKT inhibition by transfection of a dominant negative enzyme blocked RSV-induced NF-kappaB transcriptional activity. These data demonstrate that anti-apoptotic signaling and NF-kappaB activation by RSV are mediated through activation of PI 3-K-dependent pathways. Blockade of PI 3-K activation resulted in rapid, premature apoptosis and inhibition of RSV-stimulated NF-kappaB-dependent gene transcription.
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Interleukin-8 (IL-8), a chemotactic cytokine for T lymphocytes and neutrophils, is induced in several cell types by a variety of stimuli including the inflammatory cytokines IL-1 and tumor necrosis factor alpha TNF-alpha. Several cis elements, including a binding site for the inducible transcription factor NF-kappa B, have been identified in the regulatory region of the IL-8 gene. We have examined the ability of various NF-kappa B subunits to bind to, and activate transcription from, the IL-8 promoter. A nuclear complex was induced in phorbol myristate acetate-treated Jurkat T cells which bound specifically to the kappa B site of the IL-8 promoter and was inhibited by addition of purified I kappa B alpha to the reaction mixture. Only antibody to RelA (p65), but not to NFKB1 (p50), NFKB2 (p50B), c-Rel, or RelB was able to abolish binding, suggesting that RelA is a major component in these kappa B binding complexes. Gel mobility shift analysis with in vitro-translated and purified proteins indicated that whereas the kappa B element in the human immunodeficiency virus type 1 long terminal repeat bound to all members of the kappa B/Rel family examined, the IL-8 kappa B site bound only to RelA and to c-Rel and NFKB2 homodimers, but not to NFKB1 homodimers or heterodimers of NFKB1-RelA. Transient transfection analysis demonstrated a kappa B-dependent expression of the IL-8 promoter in a human fibrosarcoma cell line (8387) and in Jurkat T lymphocytes. Cotransfection with various NF-kappa B subunits indicated that RelA and c-Rel, but neither NFKB1 nor heterodimeric NFKB1-RelA, was able to activate transcription from the IL-8 promoter. Furthermore, cotransfection of NFKB1 and RelA, although able to support activation from the human immunodeficiency virus type 1 long terminal repeat, failed to activate expression from the IL-8 promoter. Antisense oligonucleotides to RelA, but not NFKB1, inhibited phorbol myristate acetate-induced IL-8 production in Jurkat T lymphocytes. These data demonstrate the differential ability of members of the kappa B/Rel family to bind to, and activate transcription from, the IL-8 promoter. Furthermore, while providing a novel example of a kappa B-regulated promoter in which the classical NF-kappa B complex is unable to activate transcription from the kappa B element, these data provide direct evidence for the role of RelA in regulation of IL-8 gene expression.