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Anticancer effects of monocarbonyl analogs of curcumin: oxidative stress, nuclear translocation and modulation of AP-1 and NF-κB
Abstract
Purpose: In order to elucidate anticancer effects of monocarbonyl analogs of curcumin (MACs), we have undertaken the present study to obtain information regarding drug targets by using a microarray approach, and to study the cellular localization of EF24 and the activity of two key transcription factors, AP-1 and NF-κB, involved in complex cellular responses of cell survival and death.
Methods: Cytotoxic activity of various drugs was evaluated using a Neutral Red Dye assay. Cellular localization of biotinylated EF24 (active) and reduced EF24 (inactive) was determined using light and confocal microscopy. Measurement of transcription factor binding was carried out using Transfactor ELISA kits (BD Clontech, Palo Alto, CA). Gene microarray processing was performed at Expression Analysis, Inc (Durham, NC) using Affymetrix Human U133A Gene Chips.
Results: In this study, we demonstrated that EF24 and UBS109 exhibit much more potent cytotoxic activity against pancreatic cancer than the current standard chemotherapeutic agent gemcitabine. EF24, rapidly localizes to the cell nucleus. The compound modulates the DNA binding activity of NF-κB and AP-1 in MDA-MB-231 human breast cancer cells and DU-145 human prostate cancer cells. Immunohistochemical studies utilizing biotinylated-EF24 and chemically-reduced EF24 show that the unsaturated compound and biotinylated EF24, but not reduced EF24, translocates to the nucleus within 30 minutes after the addition of drug. Through a gene microarray study, EF24 is shown to affect genes directly involved in cytoprotection, tumor growth, angiogenesis, metastasis and apoptosis.
Conclusion: EF24 and UBS109 warrant further investigation for development of pancreatic cancer therapy. The dualistic modulations of gene expression may be a manifestation of the cell responses for survival against oxidative stress by EF24. However, the cytotoxic action of EF24 ultimately prevails to kill the cells.
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Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003; 23:363-98.
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; 24:651-4.
Wang YJ, Pan MH, Cheng AL, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal 1997; 15:1867-76.
Shen L, Ji HF. The pharmacology of curcumin: is it the degradation products? Trends Mol Med 2012; 18:138-44.
Shetty D, Kim YJ, Shim H, Snyder JP. Eliminating the heart from the curcumin molecule: monocarbonyl curcumin mimics (MACs). Molecules 2014; 20:249-92.
Zhou T, Ye L, Bai Y, et al. Autophagy and apoptosis in hepatocellular carcinoma induced by EF25-(GSH)2: a novel curcumin analog. PLoS One 2014;9:e107876.
Zhu S, Moore TW, Lin X, et al. Synthetic curcumin analog EF31 inhibits the growth of head and neck squamous cell carcinoma xenografts. Integr Biol (Camb) 2012;4:633-40.
Zhu S, Moore TW, Morii N, et al. Synthetic curcumin analog UBS109 inhibits the growth of head and neck squamous cell carcinoma xenografts. Curr Cancer Drug Targets 2014;14:380-93.
Olivera A, Moore TW, Hu F, et al. Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int Immunopharmacol 2012;12:368-77.
Nagaraju GP, Zhu S, Wen J, et al. Novel synthetic curcumin analogues EF31 and UBS109 are potent DNA hypomethylating agents in pancreatic cancer. Cancer Lett 2013;341:195-203.
Yamaguchi M, Moore TW, Sun A, et al. Novel curcumin analogue UBS109 potently stimulates osteoblastogenesis and suppresses osteoclastogenesis: involvement in Smad activation and NF-κB inhibition. Integr Biol (Camb) 2012; 4:905-13.
Yamaguchi M, Zhu S, Weitzmann MN, et al. Curcumin analog UBS109 prevents bone marrow osteoblastogenesis and osteoclastogenesis disordered by coculture with breast cancer MDA-MB-231 bone metastatic cells in vitro. Mol Cell Biochem 2015;401:1-10.
Selvendiran K, Tong L, Vishwanath S, et al. EF24 induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by increasing PTEN expression. J Biol Chem 2007; 282:28609-18.
Subramaniam D, May R, Sureban SM, et al. Diphenyl difluoroketone: a curcumin derivative with potent in vivo anticancer activity. Cancer Res 2008; 68:1962-9.
Liang Y, Zheng T, Song R, et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology 2013; 57:1847-57.
Nagaraju GP, Zhu S, Ko JE, et al. Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer. Cancer Lett 2015; 357:557-65.
Thomas SL, Zhong D, Zhou W, et al. EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1. Cell Cycle 2008; 7:2409-17.
Sun A, Shoji M, Lu YJ, et al. Synthesis of EF24-tripeptide chloromethyl ketone: a novel curcumin-related anticancer drug delivery system. J Med Chem 2006; 49:3153-8.
Shoji M, Sun A, Kisiel W, et al. Targeting Tissue Factor-Expressing Tumor Angiogenesis and Tumors with EF24 Conjugated to Factor VIIa. J Drug Target 2008; 16:185-97.
Ndungu JM, Lu YJ, Zhu S, et al. Targeted delivery of paclitaxel to tumor cells: synthesis and in vitro evaluation. J Med Chem 2010; 53:3127-32.
Zhu S, Kisiel W, Lu YJ, et al. Visualizing cancer and response to therapy in vivo using Cy5.5-labeled factor VIIa and anti-tissue factor antibody. J Drug Target 2015;23:257-65.
Zhu S, Kisiel W, Lu YJ, et al. Tumor angiogenesis therapy using targeted delivery of Paclitaxel to the vasculature of breast cancer metastases. J Drug Deliv 2014;2014:865732.
Adams BK, Ferstl EM, Davis MC, et al. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. Bioorg Med Chem 2004;12:3871-83.
Reid JM, Buhrow SA, Gilbert JA, et al. Mouse pharmacokinetics and metabolism of the curcumin analog, 4-piperidinone,3,5-bis[(2-fluorophenyl) methylene]-acetate(3E,5E) (EF-24; NSC 716993). Cancer Chemother Pharmacol 2014;73:1137-46.
Moore TW, Zhu S, Randolph R, et al. Liver S9 Fraction-Derived Metabolites of Curcumin Analogue UBS109. ACS Med Chem Lett 2014;5: 288-92.
Usta M, Wortelboer HM, Vervoort J, et al. Human Glutathione S-Transferase-Mediated Glutathione Conjugation of Curcumin and Efflux of These Conjugates in Caco-2 Cells. Chem Res Toxicol 2007; 20:1895-902.
Awasthi S, Pandya U, Singhal SS, et al. Curcumin-glutathione interactions and the role of human glutathione S-transferase P1-1. Chem Biol Interact 2000;128:19-38.
Adams BK, Cai J, Armstrong J, et al. EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism. Anticancer Drugs 2005;16:263-75.
Sun A, Lu YJ, Hu H, et al. Curcumin analog cytotoxicity against breast cancer cells: exploitation of a redox-dependent mechanism. Bioorg Med Chem Lett 2009;19:6627-31.
Johansson MH. Reversible Michael additions: covalent inhibitors and prodrugs. Mini Rev Med Chem 2012;12:1330-44.
Serafimova IM, Pufall MA, Krishnan S, et al. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat Chem Biol 2012;8:471-6.
Potashman MH, Duggan ME. Covalent modifiers: an orthogonal approach to drug design. J Med Chem 2009;52:1231-46.
Gupta SC, Prasad S, Kim JH, et al. Multitargeting by curcumin as revealed by molecular interaction studies. Nat Prod Rep 2011;28:1937-55.
Pendurthi UR, Williams JT, Rao LV. Inhibition of tissue factor gene activation in cultured endothelial cells by curcumin. Suppression of activation of transcription factors Egr-1, AP-1, and NF-kappa B. Arterioscler Thromb Vasc Biol 1997;17:3406-13.
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;77:772-82.
Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 1995; 270:24995-5000. Erratum in: 1995;270:30235.
Chen TK, Smith LM, Gebhardt DK, et al. Activation and inhibition of the AP-1 complex in human breast cancer cells. Mol Carcinog 1996;15:215-26.
Nakshatri H, Goulet RJ Jr. NF-kappaB and breast cancer. Curr Probl Cancer 2002;26:282-309.
Mukhopadhyay A, Bueso-Ramos C, Chatterjee D, et al. Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene 2001;20:7597-609.
Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991;1072:129-57.
Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996;274:782-4.
Van Antwerp DJ, Martin SJ, Kafri T, et al. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 1996;274:787-9.
Wang CY, Mayo MW, Baldwin AS Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 1996;274:784-7.
Hollander MC, Fornace AJ Jr. Induction of fos RNA by DNA-damaging agents. Cancer Res 1989; 49:1687-92.
Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nature Cell Biol 2002;4:E131-6.
Slater AF, Stefan C, Nobel I, et al. Intracellular redox changes during apoptosis. Cell Death Differ 1996;3:57-62.
Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997;275:1132-6.
Kasinski AL, Du Y, Thomas SL, et al. Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene) piperidin-4-one (EF24), a novel monoketone analog of curcumin. Mol Pharmacol 2008; 74:654-61.
Brown A, Shi Q, Moore TW, et al. Monocarbonyl curcumin analogues: heterocyclic pleiotropic kinase inhibitors that mediate anticancer properties. J Med Chem 2013;56:3456 -66.
Landais I, Hiddingh S, McCarroll M, et al. Monoketone analogs (EF24) of curcumin, a new class of Fanconi anemia pathway inhibitors. Mol Cancer 2009;8:33- 45.
Thomas SL, Zhao J, Li Z, et al. Activation of the p38 pathway by a novel monoketone curcumin analog, EF24, suggests a potential combination strategy. Biochem Pharmacol 2010;80:1309-16.
Unruh D, Turner K, Srinivasan R, et al. Alternatively spliced tissue factor contributes to tumor spread and activation of coagulation in pancreatic ductal adenocarcinoma. Int J Cancer 2014; 134:9-20.
Chu Z, Abu-Baker S, Palascak MB, et al. Targeting and Cytotoxicity of SapC-DOPS Nanovesicles in Pancreatic Cancer. PLOS One 2013;8: e755507.
Shen Z, Peedikayil J, Olson GK, et al. Multiple transcription factor profiling by enzyme-linked immunoassay. Biotechniques 2002;32:1168,1170-2, 1174 passim.
Joshi AR, Chung CS, Son, et al. NF-kappa B activation has tissue specific effects on immune cell apoptosis during polymicrobial sepsis. Shock 2002; 18:380-6.
Benotmane AM, Hoylaerts MF, Colleen D, Belayew A. Nonisotopic quantitative analysis of protein-DNA interactions at equilibrium. Anal Biochem 1997;250:181-5.
Yates KR, Welsh J, Echrish HH, et al. Pancreatic cancer cell and microparticle procoagulant surface characterization: involvement of membrane-expressed tissue factor, phosphatidylserine and phosphatidylethanolamine. Blood Coagul Fibrinolysis 2011;22:680-7.
Haas SL, Jesnowski R, Steiner M, et al. Expression of tissue factor in pancreatic adenocarcinoma is associated with activation of coagulation. World J Gastroenterol 2006;12:4843-9.
Ran S, He J, Huang X, et al. Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice. Clin Cancer Res 2005;11:1551-62.
Kocatürk B, Van den Berg YW, Tieken C, et al. Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner. Proc Natl Acad Sci U S A 2013;110:11517-22.
van den Berg YW, Osanto S, Reitsma PH, Versteeg HH. The relationship between tissue factor and cancer progression: insights from bench and bedside. Blood 2012;119:924-32.
Kaushal V, Mukunyadzi P, Siegel ER, et al. Expression of tissue factor in prostate cancer correlates with malignant phenotype. Appl Immunohistochem Mol Morphol 2008;16:1-6.
Jobin C, Bradham CA, Russo MP, et al. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol 1999;163:3474-83.
Bergelson S, Pinkus R, Daniel V. Induction of AP-1 (Fos/Jun) by chemical agents mediates activation of glutathione S-transferase and quinone reductase gene expression. Oncogene 1994;9:565-71.
Hartsfield CL, Alam J, Choi AM. Transcriptional regulation of the heme oxygenase 1 gene by pyrrolidine dithiocarbamate. FASEB J 1998;12: 1675-82.
Yen FL, Tsai MH, Yang CM, et al. Curcumin nanoparticles ameliorate ICAM-1 expression in TNF-α-treated lung epithelial cells through p47 (phox) and MAPKs/AP-1 pathways. PLoS One 2013;8:e63845.
Jeschke J, O'Hagan HM, Zhang W, et al. Frequent inactivation of cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines. Clin Cancer Res 2013; 19:3201-11.
Musselman CA, Kutateladze TG. PHD fingers: epigenetic effectors and potential drug targets. Mol Interv 2009;9:314-23.
Malik P, Mukherjee TK. Structure-Function Elucidation of Antioxidative and prooxidative Activities of the Polyphenolic Compound Curcumin. Chinese J Biol 2014;2014:396708.
Tang NY, Huang YT, Yu CS, et al. Phenethyl isothiocyanate (PEITC) promotes G2/M phase arrest via p53 expression and induces apoptosis through caspase- and mitochondria-dependent signaling pathways in human prostate cancer DU 145 cells. Anticancer Res 2011;31:1691-702.
Owuor ED, Kong A-NT. Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol 2002;64:765-70.
Baglole CJ, Sime PJ, Phipps RP. Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione. Am J Physiol Lung Cell Mol Physiol 2008;295:L624-36.
Kong AN, Yu R, Lei W, et al. Differential activation of MAPK and ICE/Ced-3 protease in chemical-induced apoptosis: The role of oxidative stress in the regulation of mitogen-activated protein kinases (MAPKs) leading to gene expression and survival or activation of caspases leading to apoptosis. Restor Neurol Neurosci 1998;12:63-70.
DOI: http://dx.doi.org/10.14319/ijcto.32.19
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