The targets of curcumin

Current Drug Targets

Volumn 12, Issue 3, 2011, Pages 332-347

  Zhou, Hongyu ^a   Beevers, Christopher S ^a   Huang, Shile ^a  

^a LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER   (United States)

Author keywords

Curcumin; Enzymes; Growth factors; Inflammatory cytokines; Molecular targets; Protein kinases; Transcription factors

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR; ANDROGEN RECEPTOR; AROMATIC HYDROCARBON RECEPTOR; BETA CATENIN; CELL ADHESION MOLECULE; CHEMOKINE RECEPTOR CXCR4; CURCUMIN; CYCLOOXYGENASE 2; CYTOKINE; EARLY GROWTH RESPONSE FACTOR 1; ELECTROPHILE RESPONSE ELEMENT; EPIDERMAL GROWTH FACTOR RECEPTOR; ESTROGEN; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 153; GROWTH FACTOR; HYPOXIA INDUCIBLE FACTOR 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDUCIBLE NITRIC OXIDE SYNTHASE; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; NOTCH1 RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROTEIN KINASE; STAT PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR AP 1; TRANSCRIPTION FACTOR NRF2; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; DRUG BIOAVAILABILITY; DRUG DOSE ESCALATION; DRUG MECHANISM; DRUG TARGETING; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; SIGNAL TRANSDUCTION;

EID: 79551618617     PISSN: 13894501     EISSN: None     Source Type: Journal    
DOI: 10.2174/138945011794815356     Document Type: Article

References (264)

1. Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 2009; 30: 85-94.
2. Singh S. From exotic spice to modern drug? Cell 2007; 130: 765-768.
3. Kiuchi F, Goto Y, Sugimoto N, et al. Nematocidal activity of turmeric: synergistic action of curcuminoids. Chem Pharm Bull (Tokyo) 1993; 41: 1640-1643.
4. Ahsan H, Parveen N, Khan NU, et al. Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem Biol Interact 1999; 121: 161-175.
5. Sandur SK, Pandey MK, Sung B, et al. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and antiproliferative responses through a ROS-independent mechanism. Carcinogenesis 2007; 28: 1765-1773.
6. Milobedeska J, Kostanecki V, Lampe V. Structure of curcumin. Ber Dtsch Chem Ges 1910; 43: 2163-2170.
7. Lampe V, Milobedeska J. Studien über Curcumin. Ber Dtsch Chem Ges 1913; 46: 2235-2240.
8. Albert O. Turmeric (curcumin) in biliary diseases. Lancet 1937; 229: 619-621.
9. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 2009; 41: 40-59.
10. Sharma RA, Gescher AJ, Steward WP. Curcumin: the story so far. Eur J Cancer 2005; 41: 1955-1968.
11. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003; 23:363-98.
12. Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y Acad Sci 2005; 1056: 206-217.
13. Agrawal DK, Mishra PK. Curcumin and its analogues: Potential anticancer agents. Med Res Rev 2010; 30: 818-860.
14. Epstein J, Sanderson IR, Macdonald TT. Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. Br J Nutr: 1-13.
15. Takeuchi T, Ishidoh T, Iijima H, et al. Structural relationship of curcumin derivatives binding to the BRCT domain of human DNA polymerase lambda. Genes Cells 2006; 11: 223-235.
16. Leu TH, Su SL, Chuang YC, et al. Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity. Biochem Pharmacol 2003; 66: 2323-2331.
17. Fang J, Lu J, Holmgren A. Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. J Biol Chem 2005; 280: 25284-25290.
18. Reddy S, Aggarwal BB. Curcumin is a non-competitive and selective inhibitor of phosphorylase kinase. FEBS Lett 1994; 341: 19-22.
19. Skrzypczak-Jankun E, Zhou K, McCabe NP, et al. Structure of curcumin in complex with lipoxygenase and its significance in cancer. Int J Mol Med 2003; 12: 17-24.
20. Gupta KK, Bharne SS, Rathinasamy K, et al. Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding. FEBS J 2006; 273: 5320-5332.
21. Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis 2004; 6: 367-377; discussion 443-9.
22. Ishihara M, Sakagami H. Re-evaluation of cytotoxicity and iron chelation activity of three beta-diketones by semiempirical molecular orbital method. In vivo 2005; 19: 119-123.
23. Shin HK, Kim J, Lee EJ, et al. Inhibitory effect of curcumin on motility of human oral squamous carcinoma YD-10B cells via suppression of ERK and NF-kappaB activations. Phytother Res 2010; 24: 577-582.
24. Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J Neurochem 2007; 102: 522-538.
25. Rajasingh J, Raikwar HP, Muthian G, et al. Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia. Biochem Biophys Res Commun 2006; 340: 359-368.
26. Bhattacharyya S, Mandal D, Saha B, et al. Curcumin prevents tumor-induced T cell apoptosis through Stat-5a-mediated Bcl-2 induction. J Biol Chem 2007; 282: 15954-15964.
27. Bae MK, Kim SH, Jeong JW, et al. Curcumin inhibits hypoxiainduced angiogenesis via down-regulation of HIF-1. Oncol Rep 2006; 15: 1557-1562.
28. Wang Z, Zhang Y, Banerjee S, et al. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 2006; 106: 2503-2513.
29. Chen A, Xu J, Johnson AC. Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene 2006; 25: 278-287.
30. Prasad CP, Rath G, Mathur S, et al. Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem Biol Interact 2009; 181: 263-271.
31. Rinaldi AL, Morse MA, Fields HW, et al. Curcumin activates the aryl hydrocarbon receptor yet significantly inhibits (-)- benzo(a)pyrene-7R-trans-7,8-dihydrodiol bioactivation in oral squamous cell carcinoma cells and oral mucosa. Cancer Res 2002;62: 5451-5456.
32. Yan C, Jamaluddin MS, Aggarwal B, et al. Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther 2005; 4: 233-241.
33. Jung EM, Park JW, Choi KS, et al. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- mediated apoptosis through CHOP-independent DR5 upregulation. Carcinogenesis 2006; 27: 2008-2017.
34. Shishodia S, Singh T, Chaturvedi MM. Modulation of transcription factors by curcumin. Adv Exp Med Biol 2007; 595: 127-148.
35. Chen A, Xu J. Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am J Physiol Gastrointest Liver Physiol 2005; 288: G447-G456.
36. Yang C, Zhang X, Fan H, et al. Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res 2009; 1282: 133-141.
37. Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell 2008; 132: 344-362.
38. Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene 2006; 25: 6758-6780.
39. Solt LA, May MJ. The IkappaB kinase complex: master regulator of NF-kappaB signaling. Immunol Res 2008; 42: 3-18.
40. Verma IM, Stevenson JK, Schwarz EM, et al. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 1995; 9: 2723-2735.
41. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 6853-66.
42. Sovak MA, Bellas RE, Kim DW, et al. Aberrant nuclear factorkappaB/ Rel expression and the pathogenesis of breast cancer. J Clin Invest 1997; 100: 2952-2960.
43. Lu T, Sathe SS, Swiatkowski SM, et al. Secretion of cytokines and growth factors as a general cause of constitutive NFkappaB activation in cancer. Oncogene 2004; 23: 2138-2145.
44. Wang W, Abbruzzese JL, Evans DB, et al. The nuclear factorkappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5:119-127.
45. Jackson-Bernitsas DG, Ichikawa H, Takada Y, et al. Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene 2007; 26: 1385-1397.
46. Kordes U, Krappmann D, Heissmeyer V, et al. Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 2000; 14: 399-402.
47. Yang J, Richmond A. Constitutive IkappaB kinase activity correlates with nuclear factor-kappaB activation in human melanoma cells. Cancer Res 2001; 61: 4901-4909.
48. Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 1995; 270: 24995-5000.
49. Aggarwal S, Takada Y, Singh S, et al. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. Int J Cancer 2004; 111: 679-692.
50. Maillard I, Adler SH, Pear WS. Notch and the immune system. Immunity 2003; 19: 781-791.
51. Mumm JS, Kopan R. Notch signaling: from the outside in. Dev Biol 2000; 228: 151-165.
52. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol 1997; 9: 240-246.
53. Vesely PW, Staber PB, Hoefler G, et al. Translational regulation mechanisms of AP-1 proteins. Mutat Res 2009; 682: 7-12.
54. Angel P, Imagawa M, Chiu R, et al. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 1987; 49: 729-739.
55. Andreucci JJ, Grant D, Cox DM, et al. Composition and function of AP-1 transcription complexes during muscle cell differentiation. J Biol Chem 2002; 277: 16426-16432.
56. Pfarr CM, Mechta F, Spyrou G, et al. Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell 1994; 76: 747-760.
57. Bierhaus A, Zhang Y, Quehenberger P, et al. The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B. Thromb Haemost 1997; 77: 772-782.
58. Dickinson DA, Iles KE, Zhang H, et al. Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB J 2003; 17: 473-475.
59. Kang ES, Kim GH, Kim HJ, et al. Nrf2 regulates curcumininduced aldose reductase expression indirectly via nuclear factorkappaB. Pharmacol Res 2008; 58: 15-21.
60. Balogun E, Hoque M, Gong P, et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidantresponsive element. Biochem J 2003; 371: 887-895.
61. de Jong JS, van Diest PJ, van der Valk P, et al. Expression of growth factors, growth factor receptors and apoptosis related proteins in invasive breast cancer: relation to apoptotic rate. Breast Cancer Res Treat 2001; 66: 201-218.
62. Elder JT, Fisher GJ, Lindquist PB, et al. Overexpression of transforming growth factor alpha in psoriatic epidermis. Science 1989; 243: 811-4.
63. Elder LT, Klein SB, Tavakkol A, et al. Growth factor and protooncogene expression in psoriasis. J Invest Dermatol 1990; 95: 7S-9S.
64. Yarden Y, Sliwkowski M. Untangling the ErbB Signalling Network. Nat Rev Mol Cell Biol 2001; 2: 127-137.
65. Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 2006; 12: 5268-5272.
66. Burgess A, Cho H, Eigenbrot C, et al. An open-and-shut case? recent insights into the activation of EGF/ErbB Receptors. Mole Cell 2003; 12: 541-552.
67. Chen A, Xu J, Johnson A. Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene 2006; 25: 278-287.
68. Lin S, Makino K, Xia W, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 2001; 3: 802-808.
69. Lo H, Hsu S, Ali-Seyed M, et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 2005; 7: 575-589.
70. Hanada N, Lo H, Day C, et al. Co-regulation of B-Myb expression by E2F1 and EGF receptor. Mol Carcinog 2006; 45: 10-17.
71. Ahmed K, Cao N, Li J. HER-2 and NF-kappaB as targets for therapy-resistant breast cancers. Anticancer Res 2006; 26: 4235-4243.
72. Astsaturov I, Cohen R, Harari P. Targeting epidermal growth factor receptor signaling in the treatment of head and neck cancer. Expert Rev Anticancer Ther 2006; 6: 1179-1193.
73. Dancey J, Freidlin B. Targeting epidermal growth factor receptor-- are we missing the mark? Lancet 2003; 362: 62-64.
74. Korutla L, Cheung JY, Mendelsohn J, et al. Inhibition of ligandinduced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin. Carcinogenesis 1995; 16: 1741-1745.
75. Korutla L, Kumar R. Inhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells. Biochim Biophys Acta 1994; 1224: 597-600.
76. Levi-Ari S, Starr A, Vexler A, et al. Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition of Erk 1/2 activity. Anticancer Res 2006; 26: 4423-4430.
77. Hong RL, Spohn WH, Hung MC. Curcumin inhibits tyrosine kinase activity of p185neu and also depletes p185neu. Clin Cancer Res 1999; 5: 1884-1891.
78. Gasparini G. Biological and clinical role of angiogenesis in breast cancer. Breast Cancer Res Treat 1995; 36: 103-107.
79. Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal 2008; 10: 511-545.
80. Herynk MH, Fuqua SA. Estrogen receptors in resistance to hormone therapy. Adv Exp Med Biol 2007; 608: 130-143.
81. Verma SP, Goldin BR, Lin PS. The inhibition of the estrogenic effects of pesticides and environmental chemicals by curcumin and isoflavonoids. Environ Health Perspect 1998; 106: 807-812.
82. Hsing AW, Reichardt JK, Stanczyk FZ. Hormones and prostate cancer: current perspectives and future directions. Prostate 2002; 52: 213-235.
83. Ikonen T, Palvimo JJ, Kallio PJ, et al. Stimulation of androgenregulated transactivation by modulators of protein phosphorylation. Endocrinology 1994; 135: 1359-1366.
84. Nazareth LV, Weigel NL. Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem 1996; 271: 19900-19907.
85. Culig Z, Hobisch A, Cronauer MV, et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 1994; 54: 5474-5478.
86. Sato N, Sadar MD, Bruchovsky N, et al. Androgenic induction of prostate-specific antigen gene is repressed by protein-protein interaction between the androgen receptor and AP-1/c-Jun in the human prostate cancer cell line LNCaP. J Biol Chem 1997; 272: 17485-17494.
87. Fronsdal K, Engedal N, Slagsvold T, et al. CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1. J Biol Chem 1998; 273: 31853-31859.
88. Palvimo JJ, Reinikainen P, Ikonen T, et al. Mutual transcriptional interference between RelA and androgen receptor. J Biol Chem 1996; 271: 24151-24156.
89. Nakamura K, Yasunaga Y, Segawa T, et al. Curcumin downregulates AR gene expression and activation in prostate cancer cell lines. Int J Oncol 2002; 21: 825-830.
90. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50-56.
91. Ghobrial IM, Bone ND, Stenson MJ, et al. Expression of the chemokine receptors CXCR4 and CCR7 and disease progression in B-cell chronic lymphocytic leukemia/ small lymphocytic lymphoma. Mayo Clin Proc 2004; 79: 318-325.
92. Nanki T, Hayashida K, El-Gabalawy HS, et al. Stromal cellderived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol 2000; 165: 6590-6598.
93. Sameermahmood Z, Balasubramanyam M, Saravanan T, et al. Curcumin modulates SDF-1alpha/CXCR4-induced migration of human retinal endothelial cells (HRECs). Invest Ophthalmol Vis Sci 2008; 49: 3305-3311.
94. Skommer J, Wlodkowic D, Pelkonen J. Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol 2007; 35: 84-95.
95. Hasmeda M, Polya GM. Inhibition of cyclic AMP-dependent protein kinase by curcumin. Phytochemistry 1996; 42: 599-605.
96. Jurrmann N, Brigelius-Flohe R, Bol GF. Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells. J Nutr 2005; 135: 1859-64.
97. Kim GY, Kim KH, Lee SH, et al. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. J Immunol 2005; 174: 8116-8124.
98. Rafiee P, Nelson VM, Manley S, et al. Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-kappaB. Am J Physiol Gastrointest Liver Physiol 2009; 296: G388-98.
99. Johnson SM, Gulhati P, Arrieta I, et al. Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res 2009; 29: 3185-3190.
100. Shinojima N, Yokoyama T, Kondo Y, et al. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumininduced autophagy. Autophagy 2007; 3: 635-637.
101. Kizhakkayil J, Thayyullathil F, Chathoth S, et al. Modulation of curcumin-induced Akt phosphorylation and apoptosis by PI3K inhibitor in MCF-7 cells. Biochem Biophys Res Commun 2010; 394: 476-481.
102. Gururajan M, Dasu T, Shahidain S, et al. Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth. J Immunol 2007; 178: 111-121.
103. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926-1945.
104. Kim D, Sarbassov D, Ali S, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-175.
105. Grewe M, Gansauge F, Schmid R, et al. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAPp70s6K pathway in human pancreatic cancer cells. Cancer Res 1999; 59: 3581-3587.
106. Liu L, Li F, Cardelli J, et al. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 2006; 25: 7029-7040.
107. Huang S, Shu L, Easton J, et al. Inhibition of mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by suppressing protein phosphatase 5 activity. J Biol Chem 2004; 279: 36490-36496.
108. Wullschleger S, Loewith R, Hall M. TOR signaling in growth and metabolism. Cell 2006; 124: 471-484.
109. Tsang C, Bertram P, Ai W, et al. Chromatin-mediated regulation of nucleolar structure and RNA Pol I localization by TOR. EMBO J 2003; 22: 6045-6056.
110. Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 2006; 25: 6384-6391.
111. Tokunaga C, Yoshino K, Yonezawa K. mTOR integrates aminoacid and energy-sensing pathways. Biochem Biophys Res Commun 2004; 313: 443-446.
112. Kim D, Sarbassov D, Ali S, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003; 11: 895-904.
113. Sarbassov D, Sabatini D. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex. J Biol Chem 2005; 280:39505-39509.
114. Frias MA, Thoreen CC, Jaffe JD, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006; 16: 1865-1870.
115. Beevers CS, Li F, Liu L, et al. Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Int J Cancer 2006; 119: 757-764.
116. Chakraborty S, Mohiyuddin SM, Gopinath KS, et al. Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma. BMC Cancer 2008; 8: 163.
117. Darb-Esfahani S, Faggad A, Noske A, et al. Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro. J Cancer Res Clin Oncol 2009; 135: 933-941.
118. Rosenwald IB. The role of translation in neoplastic transformation from a pathologist's point of view. Oncogene 2004; 23: 3230-3247.
119. Ekstrand AI, Jonsson M, Lindblom A, et al. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer. Fam Cancer 2010; 9: 125-129.
120. Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 2004; 63: 1236-1242.
121. Riemenschneider MJ, Betensky RA, Pasedag SM, et al. AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. Cancer Res 2006; 66: 5618-5623.
122. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177-189.
123. Kim DH, Sarbassov DD, Ali SM, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrientsensitive interaction between raptor and mTOR. Mol Cell 2003; 11:895-904.
124. Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulinregulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25: 903-915.
125. Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009; 137: 873-886.
126. Fingar DC, Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004; 23: 3151-3171.
127. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-1302.
128. Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007; 405: 513-522.
129. Woo SY, Kim DH, Jun CB, et al. PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 2007; 282: 25604-25612.
130. Martin J, Masri J, Bernath A, et al. Hsp70 associates with Rictor and is required for mTORC2 formation and activity. Biochem Biophys Res Commun 2008; 372: 578-583.
131. Hresko RC, Mueckler M. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 2005; 280: 40406-40416.
132. Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098-1101.
133. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122-1128.
134. Li M, Zhang Z, Hill DL, et al. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res 2007; 67: 1988-1996.
135. Beevers CS, Chen L, Liu L, et al. Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res 2009; 69: 1000-1008.
136. Pearson G, Robinson F, Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 2001; 22: 153-183.
137. Chen YR, Tan TH. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene 1998; 17: 173-178.
138. Squires MS, Hudson EA, Howells L, et al. Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3- kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. Biochem Pharmacol 2003; 65: 361-376.
139. Weir NM, Selvendiran K, Kutala VK, et al. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther 2007; 6: 178-184.
140. Camacho-Barquero L, Villegas I, Sanchez-Calvo JM, et al. Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol 2007; 7: 333-342.
141. Munford RS, Pugin J. Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 2001; 163: 316-321.
142. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994; 12: 141-79.
143. Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest 2001; 107: 7-11.
144. Chen D, Nie M, Fan MW, et al. Anti-inflammatory activity of curcumin in macrophages stimulated by lipopolysaccharides from Porphyromonas gingivalis. Pharmacology 2008; 82: 264-269.
145. Abe Y, Hashimoto S, Horie T. Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res 1999; 39: 41-47.
146. Srimal RC, Dhawan BN. Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent. J Pharm Pharmacol 1973; 25: 447-452.
147. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104: 487-501.
148. Aggarwal BB, Shishodia S, Takada Y, et al. TNF blockade: an inflammatory issue. Ernst Schering Res Found Workshop 2006: 161-86.
149. Kuhad A, Chopra K. Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences. Eur J Pharmacol 2007; 576: 34-342.
150. Fu Y, Zheng S, Lin J, et al. Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol 2008; 73: 399-409.
151. Kumar A, Dhawan S, Hardegen NJ, et al. Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)- mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem Pharmacol 1998; 55: 775-783.
152. Dinarello CA. The paradox of pro-inflammatory cytokines in cancer. Cancer Metastasis Rev 2006; 25: 307-313.
153. Cho JW, Lee KS, Kim CW. Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alphatreated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int J Mol Med 2007; 19: 469-474.
154. Ranjan D, Chen C, Johnston TD, et al. Curcumin inhibits mitogen stimulated lymphocyte proliferation, NFkappaB activation, and IL- 2 signaling. J Surg Res 2004; 121: 171-177.
155. Kobayashi T, Hashimoto S, Horie T. Curcumin inhibition of Dermatophagoides farinea-induced interleukin-5 (IL-5) and granulocyte macrophage-colony stimulating factor (GM-CSF) production by lymphocytes from bronchial asthmatics. Biochem Pharmacol 1997; 54: 819-24.
156. Cohen AN, Veena MS, Srivatsan ES, et al. Suppression of interleukin 6 and 8 production in head and neck cancer cells with curcumin via inhibition of Ikappa beta kinase. Arch Otolaryngol Head Neck Surg 2009; 135: 190-197.
157. Wang X, Wang Q, Ives KL, et al. Curcumin inhibits neurotensinmediated interleukin-8 production and migration of HCT116 human colon cancer cells. Clin Cancer Res 2006; 12: 5346-5355.
158. Fahey AJ, Adrian Robins R, Constantinescu CS. Curcumin modulation of IFN-beta and IL-12 signalling and cytokine induction in human T cells. J Cell Mol Med 2007; 11: 1129-1137.
159. Grandjean-Laquerriere A, Antonicelli F, Gangloff SC, et al. UVBinduced IL-18 production in human keratinocyte cell line NCTC 2544 through NF-kappaB activation. Cytokine 2007; 37: 76-83.
160. Bharti AC, Donato N, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 2003; 171: 3863-3871.
161. Bachmeier BE, Mohrenz IV, Mirisola V, et al. Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis 2008; 29: 779-789.
162. Lim JH, Kwon TK. Curcumin inhibits phorbol myristate acetate (PMA)-induced MCP-1 expression by inhibiting ERK and NFkappaB transcriptional activity. Food Chem Toxicol; 48: 47-52.
163. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 2003; 24: 96-102.
164. Seibert K, Masferrer JL. Role of inducible cyclooxygenase (COX- 2) in inflammation. Receptor 1994; 4: 17-23.
165. Tiano HF, Loftin CD, Akunda J, et al. Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res 2002; 62: 3395-401.
166. Jacoby RF, Seibert K, Cole CE, et al. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 2000; 60: 5040-5044.
167. Oshima M, Murai N, Kargman S, et al. Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res 2001; 61: 1733-1740.
168. Chulada PC, Thompson MB, Mahler JF, et al. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res 2000; 60: 4705-4708.
169. Chun KS, Keum YS, Han SS, et al. Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-kappaB activation. Carcinogenesis 2003; 24: 1515-1524.
170. Kunnumakkara AB, Guha S, Krishnan S, et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 2007; 67: 3853-3861.
171. Yoysungnoen P, Wirachwong P, Bhattarakosol P, et al. Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell-implanted nude mice. Clin Hemorheol Microcirc 2006; 34: 109-115.
172. Zhang F, Altorki NK, Mestre JR, et al. Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol estertreated human gastrointestinal epithelial cells. Carcinogenesis 1999; 20: 445-451.
173. Lee YK, Park SY, Kim YM, et al. Regulatory effect of the AMPKCOX- 2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells. Ann N Y Acad Sci 2009; 1171: 489-494.
174. Lee YK, Lee WS, Hwang JT, et al. Curcumin exerts antidifferentiation effect through AMPKalpha-PPAR-gamma in 3T3-L1 adipocytes and antiproliferatory effect through AMPKalpha-COX-2 in cancer cells. J Agric Food Chem 2009; 57: 305-310.
175. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A 1968; 61: 748-755.
176. Otterbein LE, Kolls JK, Mantell LL, et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest 1999; 103: 1047-1054.
177. Amersi F, Buelow R, Kato H, et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 1999; 104: 1631-1639.
178. Vogt BA, Shanley TP, Croatt A, et al. Glomerular inflammation induces resistance to tubular injury in the rat. A novel form of acquired, heme oxygenase-dependent resistance to renal injury. J Clin Invest 1996; 98: 2139-2145.
179. Tamion F, Richard V, Bonmarchand G, et al. Induction of hemeoxygenase- 1 prevents the systemic responses to hemorrhagic shock. Am J Respir Crit Care Med 2001; 164: 1933-1938.
180. Gaedeke J, Noble NA, Border WA. Curcumin blocks fibrosis in anti-Thy 1 glomerulonephritis through up-regulation of heme oxygenase 1. Kidney Int 2005; 68: 2042-2049.
181. McNally SJ, Harrison EM, Ross JA, et al. Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. Int J Mol Med 2007; 19:165-172.
182. Mizushina Y, Dairaku I, Yanaka N, et al. Inhibitory action of polyunsaturated fatty acids on IMP dehydrogenase. Biochimie 2007; 89: 581-590.
183. Collart FR, Chubb CB, Mirkin BL, et al. Increased inosine-5'- phosphate dehydrogenase gene expression in solid tumor tissues and tumor cell lines. Cancer Res 1992; 52: 5826-5828.
184. Jayaram HN, Cooney DA, Grusch M, et al. Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis. Curr Med Chem 1999; 6: 561-74.
185. Dairaku I, Han Y, Yanaka N, et al. Inhibitory effect of curcumin on IMP dehydrogenase, the target for anticancer and antiviral chemotherapy agents. Biosci Biotechnol Biochem; 74: 185-187.
186. Chen YS, Ho CC, Cheng KC, et al. Curcumin inhibited the arylamines N-acetyltransferase activity, gene expression and DNA adduct formation in human lung cancer cells (A549). Toxicol In vitro 2003; 17: 323-333.
187. Sharma D, Sethi P, Hussain E, et al. Curcumin counteracts the aluminium-induced ageing-related alterations in oxidative stress, Na+, K+ ATPase and protein kinase C in adult and old rat brain regions. Biogerontology 2009; 10: 489-502.
188. Shimizu S, Jareonkitmongkol S, Kawashima H, et al. Inhibitory effect of curcumin on fatty acid desaturation in Mortierella alpine 1S-4 and rat liver microsomes. Lipids 1992; 27: 509-512.
189. Kohl NE, Omer CA, Conner MW, et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1995; 1: 792-797.
190. Hong J, Bose M, Ju J, et al. Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivatives: effects on cytosolic phospholipase A(2), cyclooxygenases and 5- lipoxygenase. Carcinogenesis 2004; 25: 1671-1679.
191. Mun SH, Kim HS, Kim JW, et al. Oral administration of curcumin suppresses production of matrix metalloproteinase (MMP)-1 and MMP-3 to ameliorate collagen-induced arthritis: inhibition of the PKCdelta/JNK/c-Jun pathway. J Pharmacol Sci 2009; 111: 13-21.
192. Swarnakar S, Paul S. Curcumin arrests endometriosis by downregulation of matrix metalloproteinase-9 activity. Indian J Biochem Biophys 2009; 46: 59-65.
193. Lin SS, Lai KC, Hsu SC, et al. Curcumin inhibits the migration and invasion of human A549 lung cancer cells through the inhibition of matrix metalloproteinase-2 and -9 and Vascular Endothelial Growth Factor (VEGF). Cancer Lett 2009; 285: 127-133.
194. Tsvetkov P, Asher G, Reiss V, et al. Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin. Proc Natl Acad Sci U S A 2005; 102: 5535-5540.
195. Liao YF, Hung HC, Hour TC, et al. Curcumin induces apoptosis through an ornithine decarboxylase-dependent pathway in human promyelocytic leukemia HL-60 cells. Life Sci 2008; 82: 367-375.
196. Okazaki Y, Iqbal M, Okada S. Suppressive effects of dietary curcumin on the increased activity of renal ornithine decarboxylase in mice treated with a renal carcinogen, ferric nitrilotriacetate. Biochim Biophys Acta 2005; 1740: 357-366.
197. Mukherjee Nee Chakraborty S, Ghosh U, Bhattacharyya NP, et al. Curcumin-induced apoptosis in human leukemia cell HL-60 is associated with inhibition of telomerase activity. Mol Cell Biochem 2007; 297: 31-39.
198. Lee JH, Chung IK. Curcumin inhibits nuclear localization of telomerase by dissociating the Hsp90 co-chaperone p23 from hTERT. Cancer Lett 2010; 290: 76-86.
199. Pauff JM, Hille R. Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin, and curcumin. J Nat Prod 2009; 72: 725-731.
200. Shen L, Ji HF. Insights into the inhibition of xanthine oxidase by curcumin. Bioorg Med Chem Lett 2009; 19: 5990-5993.
201. Balamurugan AN, Akhov L, Selvaraj G, et al. Induction of antioxidant enzymes by curcumin and its analogues in human islets: implications in transplantation. Pancreas 2009; 38: 454-460.
202. Kim HY, Park EJ, Joe EH, et al. Curcumin suppresses Janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia. J Immunol 2003; 171: 6072-6079.
203. Elangbam CS, Qualls CW, Jr., Dahlgren RR. Cell adhesion molecules--update. Vet Pathol 1997; 34: 61-73.
204. Bruijn JA, de Heer E. Adhesion molecules in renal diseases. Lab Invest 1995; 72: 387-394.
205. Haapasalmi K, Makela M, Oksala O, et al. Expression of epithelial adhesion proteins and integrins in chronic inflammation. Am J Pathol 1995; 147: 193-206.
206. Rajan S, Ye J, Bai S, et al. NF-kappaB, but not p38 MAP kinase, is required for TNF-alpha-induced expression of cell adhesion molecules in endothelial cells. J Cell Biochem 2008; 105: 477-486.
207. Binion DG, Heidemann J, Li MS, et al. Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NFkappaB: inhibitory role of curcumin. Am J Physiol Gastrointest Liver Physiol 2009; 297: G259-G268.
208. Milner R, Campbell IL. The integrin family of cell adhesion molecules has multiple functions within the CNS. J Neurosci Res 2002; 69: 286-291.
209. Ray S, Chattopadhyay N, Mitra A, et al. Curcumin exhibits antimetastatic properties by modulating integrin receptors, collagenase activity, and expression of Nm23 and E-cadherin. J Environ Pathol Toxicol Oncol 2003; 22: 49-58.
210. Kim HI, Huang H, Cheepala S, et al. Curcumin inhibition of integrin (alpha6beta4)-dependent breast cancer cell motility and invasion. Cancer Prev Res (Phila Pa) 2008; 1: 385-391.
211. Burz C, Berindan-Neagoe I, Balacescu O, et al. Apoptosis in cancer: key molecular signaling pathways and therapy targets. Acta Oncol 2009; 48: 811-821.
212. Singh N, Anand S. Apoptosis in health and disease. Indian J Physiol Pharmacol 1995; 39: 91-94.
213. Jee SH, Shen SC, Tseng CR, et al. Curcumin induces a p53- dependent apoptosis in human basal cell carcinoma cells. J Invest Dermatol 1998; 111: 656-661.
214. Huang MT, Wang ZY, Georgiadis CA, et al. Inhibitory effects of curcumin on tumor initiation by benzo[a]pyrene and 7,12- dimethylbenz[a]anthracene. Carcinogenesis 1992; 13: 2183-2186.
215. Conney AH, Lysz T, Ferraro T, et al. Inhibitory effect of curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin. Adv Enzyme Regul 1991; 31: 385-396.
216. Huang MT, Smart RC, Wong CQ, et al. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 1988; 48: 5941-5946.
217. Odot J, Albert P, Carlier A, et al. In vitro and in vivo anti-tumoral effect of curcumin against melanoma cells. Int J Cancer 2004; 111: 381-387.
218. Ramachandran C, Rodriguez S, Ramachandran R, et al. Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res 2005; 25: 3293-3302.
219. Shankar S, Chen Q, Sarva K, et al. Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: molecular mechanisms of apoptosis, migration and angiogenesis. J Mol Signal 2007; 2: 10.
220. Bae JH, Park JW, Kwon TK. Ruthenium red, inhibitor of mitochondrial Ca2+ uniporter, inhibits curcumin-induced apoptosis via the prevention of intracellular Ca2+ depletion and cytochrome c release. Biochem Biophys Res Commun 2003; 303: 1073-1079.
221. Anto RJ, Mukhopadhyay A, Denning K, et al. Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 2002; 23: 143-150.
222. Bharti AC, Donato N, Singh S, et al. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 2003; 101: 1053-1062.
223. Shishodia S, Amin HM, Lai R, et al. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol 2005; 70: 700-713.
224. Bush JA, Cheung KJ, Jr., Li G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp Cell Res 2001; 271: 305-314.
225. Kastan MB, Canman CE, Leonard CJ. P53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev 1995; 14: 3-15.
226. el-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817-825.
227. Basu A, Haldar S. The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death. Mol Hum Reprod 1998; 4: 1099-1109.
228. Liontas A, Yeger H. Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma. Anticancer Res 2004; 24: 987-98.
229. Choudhuri T, Pal S, Das T, et al. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner. J Biol Chem 2005; 280: 20059-20068.
230. Liu E, Wu J, Cao W, et al. Curcumin induces G2/M cell cycle arrest in a p53-dependent manner and upregulates ING4 expression in human glioma. J Neurooncol 2007; 85: 263-270.
231. Shankar S, Srivastava RK. Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer. Int J Oncol 2007; 30: 905-918.
232. Han SS, Chung ST, Robertson DA, et al. Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin Immunol 1999; 93: 152-161.
233. Moos PJ, Edes K, Mullally JE, et al. Curcumin impairs tumor suppressor p53 function in colon cancer cells. Carcinogenesis 2004; 25: 1611-1617.
234. McKinsey TA, Olson EN. Cardiac histone acetylation--therapeutic opportunities abound. Trends Genet 2004; 20: 206-213.
235. Yang XJ. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res 2004; 32: 959-976.
236. Kramer OH, Gottlicher M, Heinzel T. Histone deacetylase as a therapeutic target. Trends Endocrinol Metab 2001; 12: 294-300.
237. Lee CW, Lin WN, Lin CC, et al. Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in human tracheal smooth muscle cells: involvement of MAPKs, NF-kappaB, p300, and histone acetylation. J Cell Physiol 2006; 207: 174-186.
238. Balasubramanyam K, Varier RA, Altaf M, et al. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 2004; 279: 51163-51171.
239. Chen Y, Shu W, Chen W, et al. Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. Basic Clin Pharmacol Toxicol 2007; 101: 427-433.
240. Kunnumakkara AB, Diagaradjane P, Anand P, et al. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model. Int J Cancer 2009; 125: 2187-2197.
241. Anand P, Sundaram C, Jhurani S, et al. Curcumin and cancer: an old-age disease with an age-old solution. Cancer Lett 2008; 267: 133-164.
242. Shen SQ, Zhang Y, Xiang JJ, et al. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes. World J Gastroenterol 2007; 13: 1953-1961.
243. Wortelboer HM, Usta M, van der Velde AE, et al. Interplay between MRP inhibition and metabolism of MRP inhibitors: the case of curcumin. Chem Res Toxicol 2003; 16: 1642-1651.
244. Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res 1980; 71: 632-634.
245. Satoskar RR, Shah SJ, Shenoy SG. Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol 1986; 24: 651-654.
246. Lal B, Kapoor AK, Agrawal PK, et al. Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytother Res 2000; 14: 443-447.
247. Hatcher H, Planalp R, Cho J, et al. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 2008; 65: 1631-1652.
248. Lao CD, Ruffin MTt, Normolle D, et al. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 2006; 6: 10.
249. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001; 21: 2895-2900.
250. Shankar TN, Shantha NV, Ramesh HP, et al. Toxicity studies on turmeric (Curcuma longa): acute toxicity studies in rats, guineapigs & monkeys. Indian J Exp Biol 1980; 18: 73-75.
251. Sharma RA, McLelland HR, Hill KA, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res 2001; 7: 1894-1900.
252. Ireson CR, Jones DJ, Orr S, et al. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomarkers Prev 2002; 11: 105-111.
253. Shoba G, Joy D, Joseph T, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-356.
254. Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 2004; 10: 6847-6854.
255. Sharma RA, Ireson CR, Verschoyle RD, et al. Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. Clin Cancer Res 2001; 7: 1452-1458.
256. Holder GM, Plummer JL, Ryan AJ. The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione) in the rat. Xenobiotica 1978; 8: 761-768.
257. Perkins S, Verschoyle RD, Hill K, et al. Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev 2002; 11: 535-540.
258. Garcea G, Berry DP, Jones DJ, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev 2005; 14: 120-125.
259. Chiang PC, Lin SC, Pan SL, et al. Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells: A crucial role of AMPK and mTOR pathways. Biochem Pharmacol 2010; 79: 162-171.
260. Anand P, Nair HB, Sung B, et al. Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo. Biochem Pharmacol; 79: 330-338.
261. Maiti K, Mukherjee K, Gantait A, et al. Curcumin-phospholipid complex: Preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm 2007; 330: 155-163.
262. Adams BK, Ferstl EM, Davis MC, et al. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and antiangiogenesis agents. Bioorg Med Chem 2004; 12: 3871-3883.
263. Salmaso S, Bersani S, Semenzato A, et al. New cyclodextrin bioconjugates for active tumour targeting. J Drug Target 2007; 15: 379-390.
264. Marczylo TH, Verschoyle RD, Cooke DN, et al. Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother Pharmacol 2007; 60: 171-177