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Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells. Antioxidants (Basel) 2021; 10:antiox10101591. [PMID: 34679726 PMCID: PMC8533243 DOI: 10.3390/antiox10101591] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 12/24/2022] Open
Abstract
Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G0/G1 cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality.
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Iqbal B, Ghildiyal A, Sahabjada, Singh S, Arshad M, Mahdi AA, Tiwari S. Antiproliferative and Apoptotic Effect of Curcumin and TRAIL (TNF Related Apoptosis inducing Ligand) in Chronic Myeloid Leukaemic Cells. J Clin Diagn Res 2016; 10:XC01-XC05. [PMID: 27190933 PMCID: PMC4866231 DOI: 10.7860/jcdr/2016/18507.7579] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 02/18/2016] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Curcumin, traditionally utilized as a flavouring zest as a part of Indian cooking, has been accounted to decrease the proliferation potential of most cancer cells. Apoptosis is a mechanism by which most anticancer therapies including chemotherapy, radiation and antihormonal therapy kill tumour/cancer cells. Novel agents that may sensitize drug-resistant tumour cells for induction of apoptosis by customary treatments could lead to the regression and improved prognosis of the refractory disease. Indeed, chemotherapeutic agents have been shown to sensitize cancer cells to killing by death ligands such as tumour necrosis factor-α. AIM To investigate cytotoxicity and apoptotic effect of curcumin in chronic myeloid leukaemic cell line KCL-22. MATERIALS AND METHODS In present study, different doses of curcumin (10,25,50,75,100μM) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) (25,50 μM) alone and combine regimen were exposed to myeloid leukaemic cell KCL-22. The cell viability was monitored by MTT assay, apoptotic activity by binding of Annexin V-FITC using fluorescence microscopy and cell cycle check points by flow cytometry. RESULTS Cytotoxic assay revealed that curcumin and TRAIL induced both dose and time-dependent decrease in cell viability. Significant cell cytotoxicity was seen in combine regimen of both curcumin and TRAIL at 48 h of exposure. Cells treated with curcumin and TRAIL was arrested at the S phase, as revealed by flow cytometric analysis. Subtoxic concentrations of the curcumin-TRAIL combination induced strong apoptotic response in KCL-22 cells as demonstrated by the binding of Annexin V-FITC. CONCLUSION Our study conclude that curcumin inhibits the cancer cell growth by inducing apoptosis and enhance the therapeutic potential of TRAIL which recommends that both curcumin alone or in combination with TRAIL might be useful for leukaemic prevention and better therapeutic responses.
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Affiliation(s)
- Bushra Iqbal
- PhD Student, Department of Physiology, King George Medical University, Lucknow, India
| | - Archna Ghildiyal
- Associate Professor, Department of Physiology, King George Medical University, Lucknow, India
| | - Sahabjada
- PhD Student, Department of Zoology, Lucknow University, India
| | - Shraddha Singh
- Professor, Department of Physiology, King George Medical University, Lucknow, India
| | - Mohd. Arshad
- Professor, Department of Zoology, Lucknow University, India
| | - Abbas Ali Mahdi
- Professor and Head, Department of Biochemistry, King George Medical University, Lucknow, India
| | - Sunita Tiwari
- Professor and Head, Department of Physiology, King George Medical University, Lucknow, India
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Curcumin inhibits the invasion of thyroid cancer cells via down-regulation of PI3K/Akt signaling pathway. Gene 2014; 546:226-32. [DOI: 10.1016/j.gene.2014.06.006] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 05/18/2014] [Accepted: 06/05/2014] [Indexed: 01/14/2023]
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Heger M, van Golen RF, Broekgaarden M, Michel MC. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancer. Pharmacol Rev 2013; 66:222-307. [PMID: 24368738 DOI: 10.1124/pr.110.004044] [Citation(s) in RCA: 376] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin's distinct chemical properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coefficient, rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chemical stability of curcumin is elaborated in the context of its susceptibility to photochemical and chemical modification and degradation (e.g., alkaline hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo)chemical instability are addressed in light of pharmaceutical curcumin preparations, the use of curcumin analogues, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degradation products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metabolism as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addition to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clinical pharmacodynamics of curcumin followed by a detailed account of curcumin's direct molecular targets, whereby the phenotypical/biological changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct molecular targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.
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Affiliation(s)
- Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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Jackson SJT, Murphy LL, Venema RC, Singletary KW, Young AJ. Curcumin binds tubulin, induces mitotic catastrophe, and impedes normal endothelial cell proliferation. Food Chem Toxicol 2013; 60:431-8. [PMID: 23939039 DOI: 10.1016/j.fct.2013.08.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 08/01/2013] [Accepted: 08/04/2013] [Indexed: 12/18/2022]
Abstract
Curcumin, a component of turmeric spice that imparts flavor and color to curry, is thought to possess anti-inflammatory and antioxidant properties in biological tissues. However, while such efficacies have been described in the context of carcinogenesis, the impact of curcumin on normal cell cycle regulation is poorly understood. Here, we provide evidence of curcumin toxicity in proliferating bovine aortic endothelial cells, at concentrations relevant to the diet and below those previously reported in cancer models. Upon confirming curcumin's ability to upregulate hemeoxygenase-1 in a dose-dependent fashion, we found the minimally efficacious curcumin concentration to also inhibit endothelial cell DNA synthesis. Moreover, curcumin concentrations below the minimum 2 μM threshold required to induce hemeoxygenase-1 bound tubulin protein in vitro and triggered hallmark evidence of mitotic catastrophe in vivo. Concentrations as low as 0.1 μM curcumin led to disproportionate DNA segregation, karyorrhexis, and micronucleation in proliferating endothelial cells. While suggesting a mechanism by which physiological curcumin concentrations inhibit cell cycle progression, these findings describe heretofore unappreciated curcumin toxicity with potential implications for endothelial growth, development, and tissue healing.
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Affiliation(s)
- Steven J T Jackson
- U.S. Army Research Institute of Environmental Medicine, Military Nutrition Division, 15 Kansas Street, Natick, MA 01760, United States.
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Quitschke WW. Curcuminoid binding to embryonal carcinoma cells: reductive metabolism, induction of apoptosis, senescence, and inhibition of cell proliferation. PLoS One 2012; 7:e39568. [PMID: 22768090 PMCID: PMC3383725 DOI: 10.1371/journal.pone.0039568] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Accepted: 05/28/2012] [Indexed: 02/07/2023] Open
Abstract
Curcumin preparations typically contain a mixture of polyphenols, collectively referred to as curcuminoids. In addition to the primary component curcumin, they also contain smaller amounts of the co-extracted derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids can be differentially solubilized in serum, which allows for the systematic analysis of concentration-dependent cellular binding, biological effects, and metabolism. Technical grade curcumin was solubilized in fetal calf serum by two alternative methods yielding saturated preparations containing either predominantly curcumin (60%) or bisdemethoxycurcumin (55%). Continual exposure of NT2/D1 cells for 4–6 days to either preparation in cell culture media reduced cell division (1–5 µM), induced senescence (6–7 µM) or comprehensive cell death (8–10 µM) in a concentration-dependent manner. Some of these effects could also be elicited in cells transiently exposed to higher concentrations of curcuminoids (47 µM) for 0.5–4 h. Curcuminoids induced apoptosis by generalized activation of caspases but without nucleosomal fragmentation. The equilibrium binding of serum-solubilized curcuminoids to NT2/D1 cells incubated with increasing amounts of curcuminoid-saturated serum occurred with apparent overall dissociation constants in the 6–10 µM range. However, the presence of excess free serum decreased cellular binding in a hyperbolic manner. Cellular binding was overwhelmingly associated with membrane fractions and bound curcuminoids were metabolized in NT2/D1 cells via a previously unidentified reduction pathway. Both the binding affinities for curcuminoids and their reductive metabolic pathways varied in other cell lines. These results suggest that curcuminoids interact with cellular binding sites, thereby activating signal transduction pathways that initiate a variety of biological responses. The dose-dependent effects of these responses further imply that distinct cellular pathways are sequentially activated and that this activation is dependent on the affinity of curcuminoids for the respective binding sites. Defined serum-solubilized curcuminoids used in cell culture media are thus suitable for further investigating the differential activation of signal transduction pathways.
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Affiliation(s)
- Wolfgang W Quitschke
- Department of Psychiatry and Behavioral Science, State University of New York at Stony Brook, Stony Brook, New York, United States of America.
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Mei X, Xu D, Xu S, Zheng Y, Xu S. Novel role of Zn(II)-curcumin in enhancing cell proliferation and adjusting proinflammatory cytokine-mediated oxidative damage of ethanol-induced acute gastric ulcers. Chem Biol Interact 2012; 197:31-9. [PMID: 22465177 DOI: 10.1016/j.cbi.2012.03.006] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 02/26/2012] [Accepted: 03/11/2012] [Indexed: 12/16/2022]
Abstract
Alcohol consumption can induce gastric ulcers and zinc deficiency. Zinc complexes were reported to have anti-ulcer activity as it acts as an anti-inflammatory and antioxidant. Zn(II)-curcumin complex and its solid dispersions (SDs) were synthesized and evaluated for its gastroprotective activity and mechanism against ethanol-induced ulcer. The Swiss murine fibroblast cell line (3T3) was used as an alternative in vitro model to evaluate the effects of Zn(II)-curcumin on cell proliferation. Zn(II)-curcumin were administered orally for seven consecutive days prior to induction of ulcers using ethanol. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that solid dispersions (SDs) of Zn(II)-curcumin (2.5-20 μM) enhanced the proliferation of 3T3 cells more significantly than curcumin at the same concentrations (P<0.01). Oral administration of Zn(II)-curcumin (12, 24 and 48 mg/kg) SDs dose-dependently prevented formation of ulcer lesions induced by ethanol. The levels of proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and oxidative stress superoxide dismutase (SOD), glutathione peroxidase (GPX-Px), malonaldehyde (MDA) and H(+)-K(+)-ATPase were in the rats exposed to ethanol in ulceration have been altered. Zn(II)-curcumin prevented formation of ulcer lesions, significantly inhibited TNF-α and IL-6 mRNA expression, increased the activity of SOD and GSH-Px, reduced MDA levels and H(+)-K(+)-ATPase in mucosa of rats compared to controls (P<0.05). These findings suggest that the gastroprotective activity of Zn(II)-curcumin complex might contribute in stimulating cell proliferation and adjusting the proinflammatory cytokine-mediated oxidative damage to the gastric mucosa.
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Affiliation(s)
- Xueting Mei
- Laboratory of Traditional Chinese Medicine and Marine Drugs, Department of Biochemistry, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
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Singh P, Sarkar S, Umar S, Rengifo-Cam W, Singh AP, Wood TG. Insulin-like growth factors are more effective than progastrin in reversing proapoptotic effects of curcumin: critical role of p38MAPK. Am J Physiol Gastrointest Liver Physiol 2010; 298:G551-62. [PMID: 20133951 PMCID: PMC2853304 DOI: 10.1152/ajpgi.00497.2009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Progastrin and insulin-like growth factors (IGFs) stimulate hyperproliferation of intestinal epithelial cells (IECs) via endocrine/paracrine routes; hyperproliferation is a known risk factor for colon carcinogenesis. In the present study, inhibitory potency of curcumin in the presence or absence of progastrin and/or IGF-II was examined. Progastrin and IGF-II significantly increased proliferation of an immortalized IEC cell line, IEC-18, whereas curcumin decreased the proliferation in a dose-dependent manner. IGF-II was significantly more effective than progastrin in reversing antiproliferative effects of curcumin and reversed proapoptotic effects of curcumin by >80%; progastrin was relatively ineffective toward reversing proapoptotic effects of curcumin. IEC-18 clones were generated to overexpress either progastrin (IEC-PG) or hIGF-II (IEC-IGF). Proliferation of IEC-PG and IEC-IGF clones was increased, compared with that of control clones. Curcumin significantly reduced proliferation of IEC-PG, but not IEC-IGF, clones. Similarly, a human colon cancer cell line, Caco-2 (which expresses autocrine IGF-II), was relatively resistant to inhibitory effects of curcumin. However, Caco-2 cells treated with anti-IGF-II-antibodies were rendered sensitive to inhibitory effects of curcumin. Significant differences in inhibitory potency of curcumin against PG- vs. IGF-II-stimulated growth of IEC-18 cells were not reflected by differences in curcumin-mediated inhibition of activated (phosphorylated) ERKs/IKK(alpha/beta)/p65NF-kappaB and c-Src in wild-type (wt)IEC-18 cells, in response to the two growth factors. Surprisingly, curcumin was almost ineffective in reducing IGF-II-stimulated activation of p38MAPK but significantly reduced progastrin-stimulated phosphorylation of p38. Treatment with a p38MAPK inhibitor resulted in loss of protective effects of IGF-II against inhibitory effects of curcumin. These novel findings suggest that growth factor profile of patients and tumors may dictate inhibitory potency of curcumin and that combination of curcumin + p38MAPK inhibitor may be required for reducing hyperproliferative or tumorigenic response of IECs to endocrine and autocrine IGFs.
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Affiliation(s)
- Pomila Singh
- Dept. of Neuroscience and Cell Biology, Univ. of Texas Medical Branch, 10.104 Medical Research Bldg., 301 Univ. Blvd., Route 1043, Galveston, TX 77555-1043, USA.
| | | | | | | | | | - Thomas G. Wood
- 3Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas
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DNA damage and endoplasmic reticulum stress mediated curcumin-induced cell cycle arrest and apoptosis in human lung carcinoma A-549 cells through the activation caspases cascade- and mitochondrial-dependent pathway. Cancer Lett 2008; 272:77-90. [DOI: 10.1016/j.canlet.2008.06.031] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2008] [Revised: 04/28/2008] [Accepted: 06/30/2008] [Indexed: 11/18/2022]
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López-Lázaro M. Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent. Mol Nutr Food Res 2008; 52 Suppl 1:S103-27. [PMID: 18496811 DOI: 10.1002/mnfr.200700238] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A growing body of research suggests that curcumin, the major active constituent of the dietary spice turmeric, has potential for the prevention and therapy of cancer. Preclinical data have shown that curcumin can both inhibit the formation of tumors in animal models of carcinogenesis and act on a variety of molecular targets involved in cancer development. In vitro studies have demonstrated that curcumin is an efficient inducer of apoptosis and some degree of selectivity for cancer cells has been observed. Clinical trials have revealed that curcumin is well tolerated and may produce antitumor effects in people with precancerous lesions or who are at a high risk for developing cancer. This seems to indicate that curcumin is a pharmacologically safe agent that may be used in cancer chemoprevention and therapy. Both in vitro and in vivo studies have shown, however, that curcumin may produce toxic and carcinogenic effects under specific conditions. Curcumin may also alter the effectiveness of radiotherapy and chemotherapy. This review article analyzes the in vitro and in vivo cancer-related activities of curcumin and discusses that they are linked to its known antioxidant and pro-oxidant properties. Several considerations that may help develop curcumin as an anticancer agent are also discussed.
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Affiliation(s)
- Miguel López-Lázaro
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, Sevilla, Spain.
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Ghoneim AI. Effects of curcumin on ethanol-induced hepatocyte necrosis and apoptosis: implication of lipid peroxidation and cytochrome c. Naunyn Schmiedebergs Arch Pharmacol 2008; 379:47-60. [PMID: 18716759 DOI: 10.1007/s00210-008-0335-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2008] [Accepted: 07/06/2008] [Indexed: 11/28/2022]
Abstract
Ethanol-induced hepatocyte necrosis and apoptosis are valid in vitro models to investigate the modulatory effects of hepatoprotective/toxic agents such as curcumin. In this study, suspension and monolayer cultures of isolated rat hepatocytes were used. Levels of trypan blue uptake, reduced glutathione, and lipid peroxidation were quantified. Chromatin condensation, caspase-3 activity, and cytochrome c extramitochondrial translocation were also evaluated. Results revealed that curcumin did not protect against either ethanol-induced necrosis or glutathione depletion. Neither did curcumin reduce caspase-3 activation nor chromatin condensation. In contrast, curcumin induced glutathione depletion, caspase-3 activation, necrosis, and apoptosis. Fortunately, all tested curcumin concentrations (1 microM-10 mM) diminished the ethanol-induced lipid peroxidation. In addition, 1 microM curcumin decreased cytochrome c translocation in hepatocyte monolayers. In conclusion, low concentrations of curcumin may protect hepatocytes by reducing lipid peroxidation and cytochrome c release. Conversely, higher concentrations provoke glutathione depletion, caspase-3 activation, and hepatocytotoxicity.
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Affiliation(s)
- Asser I Ghoneim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
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Tian B, Wang Z, Zhao Y, Wang D, Li Y, Ma L, Li X, Li J, Xiao N, Tian J, Rodriguez R. Effects of curcumin on bladder cancer cells and development of urothelial tumors in a rat bladder carcinogenesis model. Cancer Lett 2008; 264:299-308. [PMID: 18342436 DOI: 10.1016/j.canlet.2008.01.041] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2007] [Revised: 01/24/2008] [Accepted: 01/28/2008] [Indexed: 12/30/2022]
Abstract
Curcumin, a well-known dietary pigment derived from Curcuma longa, inhibited growth of several types of malignant cells both in vivo and in vitro. Its effects on cell proliferation and the induction of apoptosis in human bladder cancer cell lines and intravesical activity in a rat bladder tumor model were studied. Exposure of human bladder cancer cells to curcumin resulted in the induction of apoptotic cell death and caused cells to arrest in the G2/M phase. The anti-apoptotic Bcl-2 and Survivin protein was downregulated by the curcumin treatment together with enhancement of the Bax and p53 expression. The inhibitory activities of curcumin were stronger than those of cisplatin and could not be prevented by catalase pretreatment in T24 cells. Clonal assay indicated large-dose and short-term curcumin was lethal to bladder cancer cells. Moreover, the in vivo study revealed curcumin did induce apoptosis in situ, inhibit and slow the development of bladder cancer. These observations suggest that curcumin could prove an effective chemopreventive and chemotherapy agent for bladder cancer.
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Affiliation(s)
- Binqiang Tian
- Institute of Urology, Second Hospital, Lanzhou University, 80 Cuiyingmen Street, Lanzhou, Gansu 730030, China
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Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal 2008; 10:511-45. [PMID: 18370854 DOI: 10.1089/ars.2007.1769] [Citation(s) in RCA: 437] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Curcumin is a natural polyphenol used in ancient Asian medicine. Since the first article referring to the use of curcumin to treat human disease was published in The Lancet in 1937, >2,600 research studies using curcumin or turmeric have been published in English language journals. The mechanisms implicated in the inhibition of tumorigenesis by curcumin are diverse and appear to involve a combination of antiinflammatory, antioxidant, immunomodulatory, proapoptotic, and antiangiogenic properties via pleiotropic effects on genes and cell-signaling pathways at multiple levels. The potentially adverse sequelae of curcumin's effects on proapoptotic genes, particularly p53, represent a cause for current debate. When curcumin is combined with some cytotoxic drugs or certain other diet-derived polyphenols, synergistic effects have been demonstrated. Although curcumin's low systemic bioavailability after oral dosing may limit access of sufficient concentrations for pharmacologic effects in tissues outside the gastrointestinal tract, chemical analogues and novel delivery methods are in preclinical development to overcome this barrier. This article provides an overview of the extensive published literature on the use of curcumin as a therapy for malignant and inflammatory diseases and its potential use in the treatment of degenerative neurologic diseases, cystic fibrosis, and cardiovascular diseases. Despite the breadth of the coverage, particular emphasis is placed on the prevention and treatment of human cancers.
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Olszanecki R, Gebska A, Korbut R. The Role of Haem Oxygenase-1 in the Decrease of Endothelial Intercellular Adhesion Molecule-1 Expression by Curcumin. Basic Clin Pharmacol Toxicol 2007; 101:411-5. [DOI: 10.1111/j.1742-7843.2007.00151.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Karunagaran D, Joseph J, Kumar TRS. CELL GROWTH REGULATION. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 595:245-68. [PMID: 17569215 DOI: 10.1007/978-0-387-46401-5_11] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Curcumin, the active ingredient of turmeric (Curcuma longa) used in culinary and medical practices in Asia, has immense potential for being used in cancer chemotherapy because of its control over the cell growth regulatory mechanisms. The present chapter throws light on the role of curcumin in modulating the various phases of the cell cycle and its apoptosis-inducing effects. This is followed by a discussion on the implications of these effects of curcumin for its use as a chemotherapeutic agent in cancer. Curcumin affects various cell cycle proteins and checkpoints involving downregulation of some of the cyclins and cyclin-dependent kinases, upregulation of cdk inhibitors, and inhibition of DNA synthesis. In addition, curcumin also exerts indirect control over cell division such as inhibition of telomerase activity. Remarkably, some studies point toward a selective growth-inhibitory effect of curcumin on transformed cell lines compared to nontransformed cell lines. Curcumin has also been demonstrated to have proapoptotic effects in several in vitro studies, mostly through the mitochondria-mediated pathway of apoptosis. Curcumin-mediated regulation of apoptosis involves caspases, Bcl2 family members, inhibitors of apoptosis proteins, and heat shock proteins. The accumulating data on the in vitro and in vivo actions of curcumin together with the ongoing human clinical trials will provide a better understanding of curcumin-mediated cell growth regulation, ultimately catering to the needs of human welfare.
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Affiliation(s)
- Devarajan Karunagaran
- Department of Biotechnology, Indian Institute of Technology, Madras, Chennai, India.
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Aggarwal BB, Sundaram C, Malani N, Ichikawa H. CURCUMIN: THE INDIAN SOLID GOLD. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 595:1-75. [PMID: 17569205 DOI: 10.1007/978-0-387-46401-5_1] [Citation(s) in RCA: 881] [Impact Index Per Article: 48.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".
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MESH Headings
- Animals
- Anti-Bacterial Agents/chemistry
- Anti-Bacterial Agents/pharmacology
- Anti-Bacterial Agents/therapeutic use
- Anti-Inflammatory Agents, Non-Steroidal/chemistry
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
- Antifungal Agents/chemistry
- Antifungal Agents/pharmacology
- Antifungal Agents/therapeutic use
- Antineoplastic Agents, Phytogenic/chemistry
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Agents, Phytogenic/therapeutic use
- Antioxidants/chemistry
- Antioxidants/pharmacology
- Antioxidants/therapeutic use
- Antiviral Agents/chemistry
- Antiviral Agents/pharmacology
- Antiviral Agents/therapeutic use
- Arthritis, Rheumatoid/drug therapy
- Curcuma/chemistry
- Curcumin/analogs & derivatives
- Curcumin/chemistry
- Curcumin/metabolism
- Curcumin/pharmacology
- Curcumin/therapeutic use
- Humans
- India
- Medicine, Ayurvedic
- Models, Biological
- Molecular Structure
- Neoplasms/drug therapy
- Phytotherapy
- Plants, Medicinal
- Spices
- Structure-Activity Relationship
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Affiliation(s)
- Bharat B Aggarwal
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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17
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Sharma S, Chopra K, Kulkarni SK, Agrewala JN. Resveratrol and curcumin suppress immune response through CD28/CTLA-4 and CD80 co-stimulatory pathway. Clin Exp Immunol 2007; 147:155-63. [PMID: 17177975 PMCID: PMC1810449 DOI: 10.1111/j.1365-2249.2006.03257.x] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The role of resveratrol and curcumin is well documented in cancer, inflammation, diabetes and various other diseases. However, their immunosuppressive action on T cells, B cells and macrophages is not well documented. In the present study, we have ascertained the effect of resveratrol and curcumin on T and B cells and macrophages. The most striking findings were that both resveratrol and curcumin suppressed the activity of T and B cells and macrophages, as evidenced by significant inhibition in proliferation, antibody production and lymphokine secretion. Interestingly, curcumin imparted immunosuppression by mainly down-regulating the expression of CD28 and CD80 and up-regulating CTLA-4. Resveratrol also functioned by decreasing the expression of CD28 and CD80, as well as by augmenting the production of interleukin (IL)-10.
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Affiliation(s)
- S Sharma
- Immunology Laboratory, Institute of Microbial Technology, Chandigarh, India
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18
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Kamath R, Jiang Z, Sun G, Yalowich JC, Baskaran R. c-Abl kinase regulates curcumin-induced cell death through activation of c-Jun N-terminal kinase. Mol Pharmacol 2007; 71:61-72. [PMID: 17021249 DOI: 10.1124/mol.106.026575] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Curcumin, a natural phenolic compound found in turmeric (Curcuma longa) exhibits anticancer properties, attributed to its antiproliferative and apoptosis-inducing activity. The ubiquitously expressed nonreceptor tyrosine kinase c-Abl regulates stress responses induced by oxidative agents such as ionizing radiation and H2O2. In this study, we show that c-Abl is an important component of the cell death response activated by curcumin and that Abl mediates this response partly through activation of c-Jun N-terminal kinase (JNK). Therefore, inhibition of Abl by STI571 [imatinib (Gleevec)] treatment or down-regulation of Abl expression through Abl-specific short-hairpin RNA (shRNA) diminished cell death induction and JNK activation. Highlighting the interdependent nature of the Abl and JNK signaling in the curcumin-induced cell death response, a JNK inhibitor [anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone (SP600125)] caused very little cell death inhibition in STI571-pretreated cells and in Abl shRNA-expressing cells. Moreover, treatment with Abl and JNK inhibitor alone or together caused similar levels of cell death inhibition. Although p53 induction in response to curcumin treatment is dependent on Abl, we found that Abl-->p53 signaling is not necessary for curcumin-induced cell death. Taken together, the results demonstrate the differential roles played by Abl-->p53 and Abl-->JNK signaling events in modulating the cell death response to curcumin.
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Affiliation(s)
- Ravindra Kamath
- Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1205 Biomedical Science Tower, Pittsburgh, PA 15261, USA
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19
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Sikora E, Bielak-Zmijewska A, Magalska A, Piwocka K, Mosieniak G, Kalinowska M, Widlak P, Cymerman IA, Bujnicki JM. Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells. Mol Cancer Ther 2006; 5:927-34. [PMID: 16648563 DOI: 10.1158/1535-7163.mct-05-0360] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Curcumin is a natural pigment that has been shown to induce cell death in many cancer cells; however, the death mode depends on the cell type and curcumin concentration. Here we show that, in Jurkat cells, 50 micromol/L curcumin severely lowers cell survival and induces initial stage of chromatin condensation. It also induces caspase-3, which is sufficient to cleave DNA fragmentation factor 45 [DFF45/inhibitor of caspase-activated DNase (ICAD)], the inhibitor of DFF40/CAD endonuclease. However, the release of DFF40/CAD from its inhibitor does not lead to oligonucleosomal DNA degradation in curcumin-treated cells. Moreover, curcumin treatment protects cells from UVC-induced oligonucleosomal DNA degradation. In biochemical experiments using recombinant DFF activated with caspase-3, we show that curcumin inhibits plasmid DNA and chromatin degradation although it does not prevent activation of DFF40/CAD endonuclease after its release from the inhibitor. Using DNA-binding assay, we show that curcumin does not disrupt the DNA-DFF40/CAD interaction. Instead, molecular modeling indicates that the inhibitory effect of curcumin on DFF40/CAD activity results from curcumin binding to the active center of DFF40/CAD endonuclease.
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Affiliation(s)
- Ewa Sikora
- Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, 3 Pasteura, 02-093 Warsaw, Poland.
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20
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Cheng G, Zhang X, Tang HF, Zhang Y, Zhang XH, Cao WD, Gao DK, Wang XL, Jin BQ. Asterosaponin 1, a cytostatic compound from the starfish Culcita novaeguineae, functions by inducing apoptosis in human glioblastoma U87MG cells. J Neurooncol 2006; 79:235-41. [PMID: 16628475 DOI: 10.1007/s11060-006-9136-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2006] [Accepted: 02/09/2006] [Indexed: 11/30/2022]
Abstract
Malignant glioblastoma is one of the most common malignant tumors in the neurological system. Asterosaponin 1, a new cytostatic agent from the starfish Culcita novaeguineae appear to exhibit various biological activities, including antitumor effect, but the function and mechanism of this new agent on glioblastoma cells has not previously been determined. In the present study, we investigated the proliferation change of human glioblastoma U87MG cells exposed to different concentrations (2.5-20.0 microg/ml) of asterosaponin 1 for a certain time. The results showed that asterosaponin 1 significantly suppressed U87MG cell proliferation in a time- and dose-dependent manner (IC50 =4.3 microg/ml). Flow cytometric analysis of DNA in U87MG cells showed that asterosaponin 1 induces the prominent appearance of a sub-G1 peak in the cell cycle suggestive of apoptosis identical with the result of annexin V/PI assay. Furthermore, U87MG cells treatment with asterosaponin 1 resulted in nuclear condensation with apoptotic bodies observed by both fluorescence and electron microscopy. Agarose gel electrophoresis of DNA from asterosaponin 1-treated cells revealed a typical "ladder" consistent with apoptotic DNA fragmentation. Western-blot staining showed asterosaponin 1 decreased the expression of Bcl-2 protein and increased the expression of Bax protein. The novel findings suggest that the cytostatic actions of asterosaponin 1 toward U87MG cells result from the induction of cell apoptosis. Overall, our data demonstrate that asterosaponin 1 is fully equipped for an efficient apoptotic killing of glioblastoma cells and suggest that this mechanism may play a critical role in anti-tumor chemotherapy.
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Affiliation(s)
- Guang Cheng
- Department of Neurosurgery of Xijing Hospital (Neurosurgery institute of Chinese PLA), The Fourth Military Medical University, 710032, Xi'an, ShannXi, China
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21
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Yadav VS, Mishra KP, Singh DP, Mehrotra S, Singh VK. Immunomodulatory effects of curcumin. Immunopharmacol Immunotoxicol 2005; 27:485-97. [PMID: 16237958 DOI: 10.1080/08923970500242244] [Citation(s) in RCA: 124] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Curcumin (diferuloylmethane), found in the spice turmeric, exhibits anti-inflammatory, antioxidant, and chemopreventive activities. However, the effect of curcumin on the immunological responses largely remains unknown. In this study we have investigated the effect of curcumin on mitogen (phytohaemagglutinin; PHA) stimulated T-cell proliferation, natural killer (NK) cell cytotoxicity, production of cytokines by human peripheral blood mononuclear cells (PBMCs), nitric oxide (NO) production in mouse macrophage cells, RAW-264.7. Furthermore, we have carried out an electromobility shift assay to elucidate the mechanism of action of curcumin at DNA protein interaction level. We observed that curcumin inhibits PHA-induced T-cell proliferation, interleukin-2 production, NO generation, and lipopolysachharide-induced nuclear factor-kappaB (NF-kappaB) and augments NK cell cytotoxicity. Our results suggest that curcumin most likely inhibits cell proliferation and cytokine production by inhibiting NF-kappaB target genes involved in the induction of these immune parameters.
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Affiliation(s)
- V S Yadav
- Department of Immunology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
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22
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Cui YY, Xie H, Qi KB, He YM, Wang JF. Effects of Pinus massoniana bark extract on cell proliferation and apoptosis of human hepatoma BEL-7402 cells. World J Gastroenterol 2005; 11:5277-5282. [PMID: 16149132 PMCID: PMC4622795 DOI: 10.3748/wjg.v11.i34.5277] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2004] [Revised: 11/14/2004] [Accepted: 11/19/2004] [Indexed: 02/06/2023] Open
Abstract
AIM To study the effects of Pinus massoniana bark extract (PMBE) on cell proliferation and apoptosis of human hepatoma BEL-7402 cells and to elucidate its molecular mechanism. METHODS BEL-7402 cells were incubated with various concentrations (20-200 microg/mL) of PMBE for different periods of time. After 48 h, cell proliferation was determined by 3-(4,5-dimethyl-thiazolyl-2)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis was evaluated by morphological observation, agarose gel electrophoresis, and flow cytometry analysis. Possible molecular mechanisms were primarily explored through immunohistochemical staining. RESULTS PMBE (20-200 microg/mL) significantly suppressed BEL-7402 cell proliferation in a time- and dose-dependent manner. After treatment of BEL-7402 cells with 160 microg/mL PMBE for 24, 48, or 72 h, a typical apoptotic "DNA ladder" was observed using agarose gel electrophoresis. Nuclear condensation and boundary aggregation or split, apoptotic bodies were seen by fluorescence and electron microscopy. Sub-G1 curves were displayed by flow cytometry analysis. PMBE decreased the expression levels of Bcl-2 protein in a time-dependent manner after treatment of cells with 160 microg/mL PMBE. CONCLUSION PMBE suppresses proliferation of BEL-7402 cells in a time- and dose-dependent manner and induces cell apoptosis by possibly downregulating the expression of the bcl-2 gene.
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Affiliation(s)
- Ying-Yu Cui
- The State Key Laboratory for Biocontrol and The Key Laboratory of Gene Engineering of Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, Guangdong Province, China
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23
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Joe B, Vijaykumar M, Lokesh BR. Biological properties of curcumin-cellular and molecular mechanisms of action. Crit Rev Food Sci Nutr 2005; 44:97-111. [PMID: 15116757 DOI: 10.1080/10408690490424702] [Citation(s) in RCA: 474] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Curcuminoids, a group of phenolic compounds isolated from the roots of Curcuma longa (Zingiberaceae), exhibit a variety of beneficial effects on health and on events that help in preventing certain diseases. A vast majority of these studies were carried out with curcumin (diferuloyl methane), which is a major curcuminoid. The most detailed studies using curcumin include anti-inflammatory, antioxidant, anticarcinogenic, antiviral, and antiinfectious activities. In addition, the wound healing and detoxifying properties of curcumin have also received considerable attention. As a result of extensive research on the therapeutic properties of curcumin, some understanding on the cellular, molecular, and biochemical mechanism of action of curcumin is emerging. These findings are summarized in this review.
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Affiliation(s)
- B Joe
- Department of Physiology and Molecular Medicine, Medical College of Ohio, Block Health Science Building, 3035 Arlington Avenue, Toledo, OH 43614-5804, USA.
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24
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Sharma RA, Gescher AJ, Steward WP. Curcumin: The story so far. Eur J Cancer 2005; 41:1955-68. [PMID: 16081279 DOI: 10.1016/j.ejca.2005.05.009] [Citation(s) in RCA: 1119] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2005] [Accepted: 05/13/2005] [Indexed: 01/04/2023]
Abstract
Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from curcumin's potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signalling pathways at multiple levels, effects on cellular enzymes such as cyclooxygenase and glutathione S-transferases, immuno-modulation and effects on angiogenesis and cell-cell adhesion. Curcumin's ability to affect gene transcription and to induce apoptosis in preclinical models is likely to be of particular relevance to cancer chemoprevention and chemotherapy in patients. Although curcumin's low systemic bioavailability following oral dosing may limit access of sufficient concentrations for pharmacological effect in certain tissues, the attainment of biologically active levels in the gastrointestinal tract has been demonstrated in animals and humans. Sufficient data currently exist to advocate phase II clinical evaluation of oral curcumin in patients with invasive malignancy or pre-invasive lesions of the gastrointestinal tract, particularly the colon and rectum.
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Affiliation(s)
- R A Sharma
- Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, UK.
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25
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Lee J, Im YH, Jung HH, Kim JH, Park JO, Kim K, Kim WS, Ahn JS, Jung CW, Park YS, Kang WK, Park K. Curcumin inhibits interferon-α induced NF-κB and COX-2 in human A549 non-small cell lung cancer cells. Biochem Biophys Res Commun 2005; 334:313-8. [PMID: 16005433 DOI: 10.1016/j.bbrc.2005.06.093] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2005] [Accepted: 06/18/2005] [Indexed: 10/25/2022]
Abstract
The A549 cells, non-small cell lung cancer cell line from human, were resistant to interferon (IFN)-alpha treatment. The IFN-alpha-treated A549 cells showed increase in protein expression levels of NF-kappaB and COX-2. IFN-alpha induced NF-kappaB binding activity within 30 min and this increased binding activity was markedly suppressed with inclusion of curcumin. Curcumin also inhibited IFN-alpha-induced COX-2 expression in A549 cells. Within 10 min, IFN-alpha rapidly induced the binding activity of a gamma-(32)P-labeled consensus GAS oligonucleotide probe, which was profoundly reversed by curcumin. Taken together, IFN-alpha-induced activations of NF-kappaB and COX-2 were inhibited by the addition of curcumin in A549 cells.
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Affiliation(s)
- Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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26
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Gao X, Kuo J, Jiang H, Deeb D, Liu Y, Divine G, Chapman RA, Dulchavsky SA, Gautam SC. Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro. Biochem Pharmacol 2004; 68:51-61. [PMID: 15183117 DOI: 10.1016/j.bcp.2004.03.015] [Citation(s) in RCA: 129] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2003] [Accepted: 03/19/2004] [Indexed: 12/24/2022]
Abstract
Curcumin (diferuloylmethane), a major curcumanoid found in the spice turmeric, exhibits anti-inflammatory, anti-oxidant, and chemopreventive activities. However, the effect of curcumin on the development of T cell-mediated immunological responses largely remains unknown. In this study we have investigated the effect of curcumin on mitogen/antigen induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs), lymphokine activated killer (LAK) cells, and the production of cytokines by T lymphocytes and macrophages. We found that mitogen, interleukin-2 (IL-2) or alloantigen induced proliferation of splenic lymphocytes, and development of cytotoxic T lymphocytes is significantly suppressed at 12.5-30 micromol/L curcumin. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of curcumin compared to the generation of antigen specific CTLs. Curcumin irreversibly impaired the production of these immune functions, since lymphoid cells failed to respond to the activation signals following 8h pretreatment with curcumin. Curcumin also inhibited the expression/production of IL-2 and interferon-gamma (IFN-gamma) by splenic T lymphocytes and IL-12 and tumor necrosis factor-alpha (TNF-alpha) by peritoneal macrophages irreversibly. Curcumin inhibited the activation of the transcription factor nuclear factor kappaB (NF-kappaB) without affecting the levels of constitutively expressed NF-kappaB. The latter result suggests that curcumin most likely inhibits cell proliferation, cell-mediated cytotoxicity (CMC), and cytokine production by inhibiting NF-kappaB target genes involved in induction of these immune responses.
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Affiliation(s)
- Xiaohua Gao
- Division of Surgical Research, Department of Surgery, Henry Ford Health System, One Ford Place-4D, Detroit, MI 48202, USA
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27
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Curcumin sensitizes prostate cancer cells to tumor necrosis factor–related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-κB through suppression of IκBα phosphorylation. Mol Cancer Ther 2004. [DOI: 10.1158/1535-7163.803.3.7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Abstract
Epidemiologic studies suggest that diet rich in plant-derived foods plays an important role in the prevention of prostate cancer. Curcumin, the yellow pigment in the spice turmeric, has been shown to exhibit chemopreventive and growth inhibitory activities against multiple tumor cell lines. We have shown previously that curcumin and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)/Apo2L interact to induce cytotoxicity in the LNCaP prostate cancer cell line. In this study, we investigated the mechanism by which curcumin augments TRAIL-induced cytotoxicity in LNCaP cells. Subtoxic concentrations of the curcumin-TRAIL combination induced strong apoptotic response in LNCaP cells as demonstrated by the binding of Annexin V-FITC and cleavage of procaspase-3. Furthermore, LNCaP cells express constitutively active nuclear factor-κB (NF-κB), which is inhibited by curcumin. Because NF-κB has been shown to mediate resistance to TRAIL-induced apoptosis in tumor cells, we investigated whether there is a relationship between NF-κB activation and resistance to TRAIL in LNCaP prostate cancer cells. Pretreatment with curcumin inhibited the activation of NF-κB and sensitized LNCaP cells to TRAIL. A similar increase in the sensitivity of LNCaP cells to TRAIL-induced apoptosis was observed following inhibition of NF-κB by dominant negative mutant IκBα, an inhibitor of NF-κB. Finally, curcumin was found to inhibit NF-κB by blocking phosphorylation of IκBα. We conclude that NF-κB mediates resistance of LNCaP cells to TRAIL and that curcumin enhances the sensitivity of these tumor cells to TRAIL by inhibiting NF-κB activation by blocking phosphorylation of IκBα and its degradation.
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28
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Panwalkar A, Verstovsek S, Giles F. Nuclear factor-kappaB modulation as a therapeutic approach in hematologic malignancies. Cancer 2004; 100:1578-89. [PMID: 15073843 DOI: 10.1002/cncr.20182] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Nuclear factor-kappaB (NF-kappaB) is a collective term that refers to a small class of dimeric transcription factors for a number of genes, including growth factors, angiogenesis modulators, cell-adhesion molecules, and antiapoptotic factors. Although most NF-kappaB proteins promote transcription, some act as inactivating or repressive complexes. The most common p50-RelA (p65) dimer known "specifically" as NF-kappaB, is relatively abundant, controls the expression of numerous genes, and exists as an inactive cytoplasmic complex bound to inhibitory proteins of the NF-kappaB inhibitor (IkappaB) family. The inactive NF-kappaB-IkappaB complex is activated by a variety of stimuli, including proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. The release of NF-kappaB facilitates its translocation to the nucleus, where it promotes cell survival by initiating the transcription of genes encoding stress-response enzymes, cell-adhesion molecules, proinflammatory cytokines, and antiapoptotic proteins. Constitutive activation of NF-kappaB in the nucleus is observed in some hematologic disorders. With the recent approval of bortezomib for patients with advanced multiple myeloma, NF-kappaB modulation is likely to be a therapeutic endeavor of increasing interest in coming years.
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Affiliation(s)
- Amit Panwalkar
- Section of Developmental Therapeutics, Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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29
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Wallace JM. Nutritional and botanical modulation of the inflammatory cascade--eicosanoids, cyclooxygenases, and lipoxygenases--as an adjunct in cancer therapy. Integr Cancer Ther 2004; 1:7-37; discussion 37. [PMID: 14664746 DOI: 10.1177/153473540200100102] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Emerging on the horizon in cancer therapy is an expansion of the scope of treatment beyond cytotoxic approaches to include molecular management of cancer physiopathology. The goal in these integrative approaches, which extends beyond eradicating the affected cells, is to control the cancer phenotype. One key new approach appears to be modulation of the inflammatory cascade, as research is expanding that links cancer initiation, promotion, progression, angiogenesis, and metastasis to inflammatory events. This article presents a literature review of the emerging relationship between neoplasia and inflammatory eicosanoids (PGE2 and related prostaglandins), with a focus on how inhibition of their synthesizing oxidases, particularly cyclooxygenase (COX), offers anticancer actions in vitro and in vivo. Although a majority of this research emphasizes the pharmaceutical applications of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors, these agents fail to address alternate pathways available for the synthesis of proinflammatory eicosanoids. Evidence is presented that suggests the inhibition of lipoxygenase and its by-products-LTB4, 5-HETE, and 12-HETE-represents an overlooked but crucial component in complementary cancer therapies. Based on the hypothesis that natural agents capable of modulating both lipoxygenase and COX may advance the efficacy of cancer therapy, an overview and discussion is presented of dietary modifications and selected nutritional and botanical agents (notably, omega-3 fatty acids, antioxidants, boswellia, bromelain, curcumin, and quercetin) that favorably influence eicosanoid production.
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Affiliation(s)
- Jeanne M Wallace
- Nutritional Solutions, Inc., 2935 North, 1000 East, North Logan, UT 84341, USA.
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30
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Holy JM. Curcumin disrupts mitotic spindle structure and induces micronucleation in MCF-7 breast cancer cells. Mutat Res 2002; 518:71-84. [PMID: 12063069 DOI: 10.1016/s1383-5718(02)00076-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The dietary phytochemical curcumin possesses anti-inflammatory, -oxidant, and cytostatic properties, and exhibits significant potential as a chemopreventative agent in humans. Although many cell types are arrested in the G2/M-phase of the cell cycle after curcumin treatment, the mechanisms by which this occurs are not well understood. The purpose of this study was to examine the effects of curcumin on the cell cycle of MCF-7 breast cancer cells to determine whether growth arrest is associated with structural changes in cellular organization during mitosis. For this purpose, MCF-7 breast cancer cells were treated with 10-20 microM curcumin, and the effects on cell proliferation and mitosis studied. Structural changes were monitored by immunolabeling cells with antibodies to a number of cytoplasmic and nuclear proteins, including beta-tubulin, NuMA, lamins A/C and B1, lamin B receptor, and centromere antigens. At the concentrations used, a single dose of curcumin does not induce significant apoptosis, but is highly effective in inhibiting cell proliferation for over 6 days. During the first 24-48 h of treatment, many cells are arrested in M-phase, and DNA synthesis is almost completely inhibited. Remarkably, arrested mitotic cells exhibit monopolar spindles, and chromosomes do not undergo normal anaphase movements. After 48 h, most cells eventually leave M-phase, and many form multiple micronuclei instead of individual daughter nuclei. These observations indicate that the curcumin-induced G2/M arrest previously described for MCF-7 cells is due to the assembly of aberrant, monopolar mitotic spindles that are impaired in their ability to segregate chromosomes. The production of cells with extensive micronucleation after curcumin treatment suggests that at least some of the cytostatic effects of this phytochemical are due to its ability to disrupt normal mitosis, and raises the possibility that curcumin may promote genetic instability under some circumstances.
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Affiliation(s)
- Jon M Holy
- Department of Anatomy and Cell Biology, UMD School of Medicine, 10 University Drive, Duluth, MN 55812-2487, USA.
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31
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Kang HC, Nan JX, Park PH, Kim JY, Lee SH, Woo SW, Zhao YZ, Park EJ, Sohn DH. Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro. J Pharm Pharmacol 2002; 54:119-26. [PMID: 11829122 DOI: 10.1211/0022357021771823] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
We previously demonstrated that curcumin, a well-known antioxidant, inhibits collagen deposition in carbon tetrachloride-induced liver injury in rats. The major effector cells responsibleforcollagensynthesis in the liver are activated hepatic stellate cells. In this study,we investigated the inhibitory effects of curcumin on the collagen synthesis and activation of rat hepatic stellate cells in-vitro, and on hepatic stellate cell activation in-vivo. The effects of curcumin on the production of collagen and smooth muscle alpha-actin proteins and of alpha1(I) collagen mRNA were studied in-vivo and in-vitro. The effect of curcumin on DNA synthesis was also determined in-vitro. In-vivo, treatment with curcumin reduced collagen deposition and smooth muscle alpha-actin-positive areas and lowered mRNA levels of type I collagen in the liver. In-vitro, curcumin at a concentration of 5 microg mL(-1) reduced DNA synthesis, and downregulated smooth muscle alpha-actin and type I collagen expression, and alpha1(I) collagen mRNA expression. We concluded that curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro, and thus may prove a valuable anti-fibrogenic agent.
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Affiliation(s)
- Hee-Chul Kang
- Department of Pharmacy, Medicinal Resources Research Center, Wonkwang University, Iksan, Jeonbuk, South Korea
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32
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Abstract
PURPOSE The development of an effective nontoxic intravesical agent that may be used immediately after bladder tumor resection to prevent the implantation of tumor cells would be a significant clinical advancement. We report the cytotoxic effects of curcumin on bladder tumor cell lines as well as its effects on the intravesical implantation of tumor cells in C3H mice. MATERIALS AND METHODS UMUC human and MBT-2 mouse bladder cancer lines were incubated with 0 to 100 microM. curcumin in dimethyl sulfoxide for 30 minutes and cell viability was determined by clonal assay. Additional culture dishes were incubated with curcumin and processed for electron microscopy. Using the C3H mice and the MBT2 tumor lines the effects of intravesical curcumin on tumor implantation after bladder injury was studied. The 10 group 1 mice served as nontreatment controls. In the 18 group 2 mice 30 minutes after tumor cell implantation 100 microM. curcumin in 0.1% dimethyl sulfoxide were instilled intravesically for 30 minutes. The 15 group 3 mice served as treatment controls with 0.1% dimethyl sulfoxide or culture medium instilled intravesically for 30 minutes. Animals were sacrificed 7 to 10 days after treatment and the bladder was subjected to histological analysis for tumor. RESULTS At the 100 microM. dose curcumin was completely lethal to the 2 cell lines on clonal growth assay. Electron microscopy revealed apoptotic bodies after curcumin administration. The tumor implantation rate was 16.7% (3 of 18 mice) in curcumin treated bladders and 73% (11 of 15) in the vehicle control group. CONCLUSIONS At the 100 microm. concentration curcumin is a potent cytotoxic agent against the MBT and UMUC bladder tumor cell lines. In addition, curcumin effectively inhibits tumor implantation and growth in this murine bladder tumor model.
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SINDHWANI PUNEET, HAMPTON JAMESA, BAIG MIRZAM, KECK RICK, SELMAN STEVENH. CURCUMIN PREVENTS INTRAVESICAL TUMOR IMPLANTATION OF THE MBT-2 TUMOR CELL LINE IN C3H MICE. J Urol 2001. [DOI: 10.1016/s0022-5347(05)65819-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- PUNEET SINDHWANI
- From the Departments of Urology and Pathology, Medical College of Ohio, Toledo, Ohio
| | - JAMES A. HAMPTON
- From the Departments of Urology and Pathology, Medical College of Ohio, Toledo, Ohio
| | - MIRZA M. BAIG
- From the Departments of Urology and Pathology, Medical College of Ohio, Toledo, Ohio
| | - RICK KECK
- From the Departments of Urology and Pathology, Medical College of Ohio, Toledo, Ohio
| | - STEVEN H. SELMAN
- From the Departments of Urology and Pathology, Medical College of Ohio, Toledo, Ohio
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Abstract
Muitos compostos presentes nos alimentos, tanto naturalmente, como adicionados ou produzidos durante o processamento, já foram testados quanto à mutagenicidade ou antimutagenicidade em diferentes sistemas experimentais. O grande número de corantes para alimentos, naturais ou sintéticos, tem levado os pesquisadores a avaliar a mutagenicidade e/ou antimutagenicidade desses compostos. Alguns corantes sintéticos apresentaram potencial mutagênico e seu uso foi proibido em alguns países. Muitos corantes naturais testados apresentaram potencial antimutagênico em pelo menos um sistema-teste, entretanto, isto não quer dizer que os corantes naturais são inócuos. O corante natural curcumina, por exemplo, apresentou potencial antimutagênico nos testes in vivo e foi mutagênico nos testes in vitro. Este paradoxo ressalta a importância de uma avaliação criteriosa e ampla na avaliação da possível atividade mutagênica e/ou antimutagênica dos corantes.
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Anto RJ, Maliekal TT, Karunagaran D. L-929 cells harboring ectopically expressed RelA resist curcumin-induced apoptosis. J Biol Chem 2000; 275:15601-4. [PMID: 10747850 DOI: 10.1074/jbc.c000105200] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Curcumin (diferuloyl methane), the yellow pigment in turmeric (Curcuma longa), is a potent chemopreventive agent. Curcumin induces apoptosis of several, but not all, cancer cells. Many cancer cells protect themselves against apoptosis by activating nuclear factor-kappaB (NF-kappaB)/Rel, a transcription factor that helps in cell survival. Signal-induced activation of NF-kappaB is known to be inhibited by curcumin. To understand the role of NF-kappaB in curcumin-induced apoptosis, we stably transfected relA gene encoding the p65/RelA subunit of NF-kappaB, into l-929 cells (mouse fibrosarcoma) and the relA-transfected cells were resistant to varying doses of curcumin (10(-6)-10(-4) m), whereas the parental cells underwent apoptosis in a time- and dose-dependent manner. The relA-transfected cells showed constitutive NF-kappaB DNA binding activity that could not be inhibited by curcumin and did not show nuclear condensation and DNA fragmentation upon treatment with curcumin. When a super-repressor form of IkappaB-alpha (known to inhibit NF-kappaB) was transfected transiently into relA-transfected cells, the cells were no longer resistant to curcumin. Our results highlight a critical anti-apoptotic role for NF-kappaB in curcumin-induced apoptosis.
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Affiliation(s)
- R J Anto
- Division of Cancer Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala-695014, India
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