Advertisement

Comparative binding studies of curcumin and tangeretin on up-stream elements of NF-kB cascade: a combined molecular docking approach

  • Srinivasulu CheemanapalliEmail author
  • Nagaraju Chinthakunta
  • Nagoor Meeravali Shaikh
  • Vutharadhi Shivaranjani
  • Ramachandra Reddy Pamuru
  • Suresh Kumar Chitta
Original Article
  • 84 Downloads

Abstract

The hyper-activation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) in cellular system is associated with inflammation, cancer and other human diseases. The core elements of NF-kB cascade might regulate the translocation and activation of NF-kB transcription factor. In the present study, we focused on active site analysis and molecular docking studies of core elements of NF-kB pathway. Curcumin and tangeretin are the natural compounds used as ligands in this docking study. We performed comparative docking studies by applying individual and combination of ligands on drug target proteins (NF-kB core elements). The docking energy and active site residues interacts with curcumin and tangeretin were obtained as follows: IKK complex (− 4.13 kcal/mol; Leu737, Asp738, Trp739, Lys96 and − 2.76 kcal/mol; Thr735, Ser733), proteosome (− 4.38 kcal/mol; Gln49, Asp52, Arg42, Glu24 and − 4.05 kcal/mol; Asp52), RelA (− 6.00 kcal/mol; Arg304, Thr308, Arg302 and − 3.46 kcal/mol; Arg302, Thr305) and NF-kB (− 5.42 kcal/mol; Cys359, Lys445, Lys541, Glu360 and − 5.31 kcal/mol; Lys444, Tyr357), respectively. Hex combined docking score obtained for IKK complex; proteosome, RelA and NF-kB are − 88.28, − 98.64, − 53.89 and − 80.55 kcal/mol, respectively. In this study, we found that proteosome has shown the highest docking energy (− 98.64 kcal/mol) and it is suggested to be as crucial drug target in NF-kB cascade. However, further experimental and clinical verification is needed for clear evidence.

Keywords

NF-kB Cancer Inflammation Curcumin Tangeretin Proteosome RelA HEX docking 

Notes

References

  1. Adam SA, Gerace L (1991) Cytosolic proteins that specifically bind nuclear location signals are receptors for nuclear import. Cell 66:837–847Google Scholar
  2. Al-Qubaisi M, Rozita R, Yeap SK, Omar AR, Ali AM, Alitheen NB (2011) Selective cytotoxicity of goniothalamin against hepatoblastoma HepG2 cells. Molecules 16(4):2944–2959Google Scholar
  3. Amschler K, Schön MP, Pletz N, Wallbrecht K, Erpenbeck L, Schön M (2010) NF-kappaB inhibition through proteasome inhibition or IKKbeta blockade increases the susceptibility of melanoma cells to cytostatic treatment through distinct pathways. J Invest Dermatol 130(4):1073–1086Google Scholar
  4. Arafa-el SA, Zhu Q, Barakat BM, Wani G, Zhao Q, El-Mahdy MA, Wani AA (2009) Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through down-regulation of phosphoinositide 3-kinase/Akt signaling pathway. Cancer Res 69(23):8910–8917Google Scholar
  5. Baeuerle PA, Henkel T (1994) Function and activation of NFkB in immune system. Annu Rev Immunol 12:141–179Google Scholar
  6. Baeurle PA, Baltimore D (1996) NFkB: Ten years after. Cell 87:13–20Google Scholar
  7. Baldwin AS Jr (1996) The NFkappaB and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683Google Scholar
  8. Baldwin AS (2001) Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 107:241–246Google Scholar
  9. Banerjee S, Ji C, Mayfield JE, Goel A, Xiao J, Dixon JE, Guo X (2018) Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2. Proc Natl Acad Sci USA 115(32):8155–8160Google Scholar
  10. Binkowski AT, Naghibzadeh S, Liang JJ (2003) CASTp: computed atlas of surface topography of proteins. Nucleic Acids Res 32:3352–3355Google Scholar
  11. Bracke ME, Depypere HT, Boterberg T, Van Marck VL, Vennekens KM, Vanluchene E, Nuytinck M, Serreyn R, Mareel MM (1999) Influence of tangeretin on tamoxifen’s therapeutic benefit in mammary cancer. J Natl Cancer Inst 91(4):354–359Google Scholar
  12. Cai YY, Lin WP, Li AP, Xu JY (2013) Combined effects of curcumin and triptolide on an ovarian cancer cell line. Asian Pac J Cancer Prev 14(7):4267–4271Google Scholar
  13. Carvalho G, Fabre C, Braun T, Grosjean J, Ades L, Agou F, Tasdemir E, Boehrer S, Israel A, Véron M, Fenaux P, Kroemer G (2007) Inhibition of NEMO, the regulatory subunit of the IKK complex, induces apoptosis in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene 26(16):2299–2307Google Scholar
  14. Chen H, Zhang ZS, Zhamng YL, Zhou DY (1999) Curcumin inhibits cell proliferation by interfering with the cell cycle and inducing apoptosis in colon carcinoma cells. Anticancer Res 19:3675–3680Google Scholar
  15. Chen H, Huang Q, Dong J, Lan Q (2006) Cancer initiating cell theory: popularity and controversies. Ai Zheng 25(6):779–784Google Scholar
  16. Choi S, Ko H, Ko S, Hwang J, Park J, Kang S, Han S, Yun S, Kim S (2007) Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol Pharm Bull 30(4):772–778Google Scholar
  17. Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G (2002) Curcumin induces apoptosis in human breast cancer cells through p53-dependent Bax induction. FEBS Lett 512(1–3):334–340Google Scholar
  18. Csaki C, Mobasheri A, Shakibaei M (2009) Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis. Arthritis Res Ther 11(6):R165Google Scholar
  19. Delano WL (2006) The PyMOL molecular graphics system. Delano Scientific, San Carlos, CAGoogle Scholar
  20. Denz U, Haas PS, Wäsch R, Einsele H, Engelhardt M (2006) State of the art therapy in multiple myeloma and future perspectives. Eur J Cancer 42:1591–1600Google Scholar
  21. Eun SH, Woo JT, Kim DH (2017) Tangeretin inhibits IL-12 expression and NF-κB activation in dendritic cells and attenuates colitis in mice. Planta Med 83(6):527–533Google Scholar
  22. Garg A, Aggarwal BB (2002) Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 16(6):1053–1068Google Scholar
  23. Ghosh S, May MJ, Kopp EB (1998) NFkB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260Google Scholar
  24. Guo JJ, Li YJ, Xin LL (2015) Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of notch signaling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3K)/AKt/mTOR pathways. Bangladesh J Pharmacol 10:937–947Google Scholar
  25. Gupta SC, Sundaram C, Reuter S, Aggarwal BB (2010) Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 1799(10–12):775–787Google Scholar
  26. Huang TS, Lee SC, Lin JK (1991) Supression of cJun/AP-1 activation by an inhibitor of tumour promotion in mouse fibroblast cells. Proc Natl Acad Sci USA 88:5292Google Scholar
  27. Huey R, Morris GM, Olson AJ, Goodsell DSJ (2007) Comp. Chem 28:145–152Google Scholar
  28. Iqbal B, Ghildiyal A, Singh S, Siddiqui S, Kumari P, Arshad M, Mahdi AA (2018) combinatorial effect of curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in induction of apoptosis via inhibition of nuclear factor kappa activity and enhancement of caspase-3 activity in chronic myeloid cells: an in-vitro study. J Cancer Res Ther 14(Supplement):S1193–S1200Google Scholar
  29. Israël A (2010) The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol 2(3):a000158Google Scholar
  30. Ivanov VN, Bhoumik A, Ronai Z (2003) Death receptors and melanoma resistance to apoptosis. Oncogene 22:3152–3161Google Scholar
  31. Jana NR, Dikshit P, Goswami A, Nukina N (2004) Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway. J Biol Chem 279:11680–11685Google Scholar
  32. Jang SE, Ryu KR, Park SH, Chung S, Teruya Y, Han MJ, Woo JT, Kim DH (2013) Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38. Int Immunopharmacol 17(3):502–507Google Scholar
  33. Kane RC, Dagher R, Farrell A, Ko CW, Sridhara R, Justice R, Pazdur R (2007) Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 13:5291–5294Google Scholar
  34. Karin M (2006) Nuclear factor-κB in cancer development and progression. Nature 441(7092):431–436Google Scholar
  35. Kim SG, Veena MS, Basak SK, Han E, Tajima T, Gjertson DW, Starr J, Eidelman O, Pollard HB, Srivastava M, Srivatsan ES, Wang MB (2011) Curcumin treatment suppresses IKKβ kinase activity of salivary cells of patients with head and neck cancer: a pilot study. Clin Cancer Res 17(18):5953–5961Google Scholar
  36. Kim JH, Gupta SC, Park B, Yadav VR, Aggarwal BB (2012) Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis. Mol Nutr Food Res 56(3):454–465Google Scholar
  37. Kumar A, Dhawan S, Hardegen NJ, Aggarwal BB (1998) Curcumin (diferuloylmethane) inhibition of tumour necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor kB activation. Biochem Pharmacol 55:775Google Scholar
  38. Kuo ML, Huang TS, Lin JK (1996) Curcumin, an antioxidant and anti-tumour promoter, induces apoptosis in human leukemia cells. Biochim Biophysical Acta 1317:95–100Google Scholar
  39. Ludwig H, Khayat D, Giaccone G, Facon T (2005) Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. Cancer 104:1794–1807Google Scholar
  40. Marquardt JU, Gomez-Quiroz L, Arreguin Camacho LO, Pinna F, Lee YH, Kitade M, Domínguez MP, Castven D, Breuhahn K, Conner EA, Galle PR, Andersen JB, Factor VM, Thorgeirsson SS (2015) Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. J Hepatol 63(3):661–669Google Scholar
  41. Meiyanto E, Fitriasari A, Hermawan A, Junedi S, Susidarti RA (2011) The improvement of doxorubicin activity on breast cancer cell lines by tangeretin through cell cycle modulation. Orient Pharm Exp Med 11(3):183–190Google Scholar
  42. Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352(5):476–487Google Scholar
  43. Parasramka MA, Gupta SV (2012) Synergistic effect of garcinol and curcumin on antiproliferative and apoptotic activity in pancreatic cancer cells. J Oncol 2012:709739Google Scholar
  44. Rusha M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S (2008) Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure 16:798–808CrossRefGoogle Scholar
  45. Milacic V, Banerjee S, Landis-Piwowar KR, Sarkar FH, Majumdar AP, Dou QP (2008) Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo. Cancer Res 68(18):7283–7292Google Scholar
  46. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK (1999) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662Google Scholar
  47. Nautiyal J, Kanwar SS, Yu Y, Majumdar AP (2011) Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal 6:7Google Scholar
  48. Notarbartolo M, Poma P, Perri D, Dusonchet L, Cervello M, D’Alessandro N (2005) Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression. Cancer Lett 224(1):53–65Google Scholar
  49. Olivera A, Moore TW, Hu F, Brown AP, Sun A, Liotta DC, Snyder JP, Yoon Y, Shim H, Marcus AI, Miller AH, Pace TW (2012) 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 12(2):368–377Google Scholar
  50. Pan MH, Chen WJ, Shiau SYL, Ho CT, Lin JK (2002) Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis 23(10):1677–1684Google Scholar
  51. Patel PB, Thakkar VR, Patel JS (2015) Cellular effect of curcumin and citral combination on breast cancer cells: induction of apoptosis and cell cycle arrest. J Breast Cancer 18(3):225–234Google Scholar
  52. Ravindran J, Prasad S, Aggarwal BB (2009) Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J 11(3):495–510Google Scholar
  53. Rooprai HK, Kandanearatchi A, Maidment SL, Christidou M, Trillo-Pazos G, Dexter DT, Rucklidge GJ, Widmer W, Pilkington GJ (2001) Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro. Neuropathol Appl Neurobiol 27:29–39Google Scholar
  54. Seo MB, Lee SK, Jeon YJ, Im JS (2011) Inhibition of p65 nuclear translocation by baicalein. Toxicol Res 27(2):71–76Google Scholar
  55. Sethi G, Sung B, Aggarwal BB (2008) Nuclear factor-kappaB activation: from bench to bedside. Exp Biol Med (Maywood) 233(1):21–31Google Scholar
  56. Singh S, Aggrawal BB (1995) Activation of transcription factor NFkB is suppressed by curcumin. J Biol Chem 270:24995Google Scholar
  57. Sinha D, Biswas J, Sung B, Aggarwal BB, Bishayee A (2012) Chemopreventive and chemotherapeutic potential of curcumin in breast cancer. Curr Drug Targets 13(14):1799–1819Google Scholar
  58. Traenckner EB, Wilk S, Baeuerle PA (1994) A proteosome inhibitor prevents activation of NFkB and stabilizes a newly phosphorylated form of I-kBα that is still bound to NFkB. EMBO J 15:5433–5441Google Scholar
  59. Urban MB, Baeurle PA (1975) The 65-Kd subunit of NFkB is a receptor for IkB and a modulator of DNA binding specificity. Genes Dev 4:1975–1984Google Scholar
  60. Verma IM, Stevenson JK, Schwarz EM, Antwerp D, Miyamoto S (1995) (1995) Rel/NFkB/IkB family: innate tales of association and dissociation. Genes Dev 9:2723–2735Google Scholar
  61. Walters DK, Muff R, Langsam B, Born W, Fuchs B (2008) Cytotoxic effects of curcumin on osteosarcoma cell lines. Invest New Drugs 26(4):289–297Google Scholar
  62. Wang K, Zhang C, Bao J, Jia X, Liang Y, Wang X, Chen M, Su H, Li P, Wan J, He C (2016) Synergistic chemopreventive effects of curcumin and berberine on human breast cancer cells through induction of apoptosis and autophagic cell death. Sci Rep 6:26064Google Scholar
  63. Yamamoto Y, Gaynor RB (2001) Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 107(2):135–142Google Scholar
  64. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, Israel A (1998) Complementation cloning of NEMO, a component of the IkB kinase complex essential for NFkB activation. Cell 93:1231–1240Google Scholar
  65. Yanez J, Vicente V, Miguel A, Castillo J, Benavente-García O, Canteras M, Teruel JA (2004) Cytotoxicity and antiproliferative activities of several phenolic compounds against three melanocytes cell lines: relationship between structure and activity. Nutr Cancer 49(2):191–199Google Scholar
  66. Zeligs KP, Neuman MK, Annunziata CM (2016) Molecular pathways: the balance between cancer and the immune system challenges the therapeutic specificity of targeting nuclear factor-κB signaling for cancer treatment. Clin Cancer Res 22(17):4302–4308Google Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of BiochemistryYogi Vemana UniversityKadapaIndia
  2. 2.Department of BiochemistrySri Krishnadevaraya UniversityAnantapuramuIndia
  3. 3.Department of BotanyYogi Vemana UniversityKadapaIndia

Personalised recommendations