Skip to main content
SpringerLink
Log in

The Role of Indirubins in Inflammation and Associated Tumorigenesis

  • Chapter
  • First Online:
Drug Discovery from Mother Nature

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 929))

Abstract

Indirubin is the major active component of an herbal recipe ‘Dangui Luhui Wan’ (当归芦荟丸) in traditional Chinese medicine (TCM). It is widely used in China for the treatment of inflammation, cancer, and other chronic diseases and is known for good efficiency and very low side effects. Primary studies on the mechanism of action revealed that indirubin and derivatives are potent ATP-competitive inhibitors of CDKs and GSK3ß achieving IC50 values down to the low nanomolar range. However, the clinical application of indirubins is limited by the extremely poor water solubility (<1 mg/L in general) and consequently the insufficient bioavailability originating from strong binding forces in the crystal lattice. In the last few decades, a lot of efforts had been put into the structure optimization of indirubin derivatives binding selectively to specific kinases. Thus, a number of new indirubins have been developed bearing substituents mainly in the 5- and 3′-position suitable for improved solubility and inhibition against CDKs and GSK3ß, referred to as canonical indirubins. Interestingly, several noncanonical 7- and 7′-indirubin derivatives have been reported, showing a distinct binding model in the ATP-binding pocket and targeting a very different spectrum of protein kinases as seen from kinase profiling. In this chapter, we will review the field of indirubin research from its discovery, synthesis, chemical modification, structure-activity relationship, and mechanism of action to molecular targets comprising recent advantages and new findings in the context of inflammation-associated signaling pathways, in particular in tumorigenesis, including NF-κB, STAT3, TGF-ß, and AhR.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Adachi J, Mori Y, Matsui S, Matsuda T (2004) Comparison of gene expression patterns between 2,3,7,8-tetrachlorodibenzo-p-dioxin and a natural arylhydrocarbon receptor ligand, indirubin. Toxicol Sci 80(1):161–169. doi:10.1093/toxsci/kfh129

    Article  CAS  PubMed  Google Scholar 

  2. Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller CA 3rd, Kato T, Saeki K, Matsuda T (2001) Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J Biol Chem 276(34):31475–31478. doi:10.1074/jbc.C100238200

    Article  CAS  PubMed  Google Scholar 

  3. Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6(3):203–208. doi:10.1016/j.ccr.2004.09.003

    Article  CAS  PubMed  Google Scholar 

  4. Aggarwal BB, Vijayalekshmi RV, Sung B (2009) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15(2):425–430. doi:10.1158/1078-0432.CCR-08-0149

    Article  CAS  PubMed  Google Scholar 

  5. Ahn MY, Kim TH, Kwon SM, Yoon HE, Kim HS, Kim JI, Kim YC, Kang KW, Ahn SG, Yoon JH (2015) 5-nitro-5′-hydroxy-indirubin-3′-oxime (AGM130), an indirubin-3′-oxime derivative, inhibits tumor growth by inducing apoptosis against non-small cell lung cancer in vitro and in vivo. Eur J Pharm Sci 79:122–131. doi:10.1016/j.ejps.2015.08.015

    Article  CAS  PubMed  Google Scholar 

  6. Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D, Massague J (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139(4):757–769. doi:10.1016/j.cell.2009.09.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alborzinia H, Schmidt-Glenewinkel H, Ilkavets I, Breitkopf-Heinlein K, Cheng X, Hortschansky P, Dooley S, Wolfl S (2013) Quantitative kinetics analysis of BMP2 uptake into cells and its modulation by BMP antagonists. J Cell Sci 126(Pt 1):117–127. doi:10.1242/jcs.109777

    Article  CAS  PubMed  Google Scholar 

  8. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB (2008) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25(9):2097–2116. doi:10.1007/s11095-008-9661-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baeyer A (1881) Ueber die Verbindungen der Indigogruppe. Chem Ber 14:1741–1750

    Article  Google Scholar 

  10. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545. doi:10.1016/S0140-6736(00)04046-0

    Article  CAS  PubMed  Google Scholar 

  11. Beauchard A, Ferandin Y, Frere S, Lozach O, Blairvacq M, Meijer L, Thiery V, Besson T (2006) Synthesis of novel 5-substituted indirubins as protein kinases inhibitors. Bioorg Med Chem 14(18):6434–6443. doi:10.1016/j.bmc.2006.05.036

    Article  CAS  PubMed  Google Scholar 

  12. Benson JM, Shepherd DM (2011) Dietary ligands of the aryl hydrocarbon receptor induce anti-inflammatory and immunoregulatory effects on murine dendritic cells. Toxicol Sci 124(2):327–338. doi:10.1093/toxsci/kfr249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Blanz J, Ehninger G, Zeller KP (1989) The isolation and identification of indigo and indirubin from urine of a patient with leukemia. Res Commun Chem Pathol Pharmacol 64(1):145–156

    CAS  PubMed  Google Scholar 

  14. Blazevic T, Heiss EH, Atanasov AG, Breuss JM, Dirsch VM, Uhrin P (2015) Indirubin and indirubin derivatives for counteracting proliferative diseases. Evid Based Complement Alternat Med 2015:654098. doi:10.1155/2015/654098

    Article  PubMed  PubMed Central  Google Scholar 

  15. Blazevic T, Schaible AM, Weinhaupl K, Schachner D, Nikels F, Weinigel C, Barz D, Atanasov AG, Pergola C, Werz O, Dirsch VM, Heiss EH (2014) Indirubin-3′-monoxime exerts a dual mode of inhibition towards leukotriene-mediated vascular smooth muscle cell migration. Cardiovasc Res 101(3):522–532. doi:10.1093/cvr/cvt339

    Article  CAS  PubMed  Google Scholar 

  16. Braig S, Kressirer CA, Liebl J, Bischoff F, Zahler S, Meijer L, Vollmar AM (2013) Indirubin derivative 6BIO suppresses metastasis. Cancer Res 73(19):6004–6012. doi:10.1158/0008-5472.CAN-12-4358

    Article  CAS  PubMed  Google Scholar 

  17. Broecker-Preuss M, Becher-Boveleth N, Gall S, Rehmann K, Schenke S, Mann K (2015) Induction of atypical cell death in thyroid carcinoma cells by the indirubin derivative 7-bromoindirubin-3′-oxime (7BIO). Cancer Cell Int 15:97. doi:10.1186/s12935-015-0251-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao YX, Pestell RG, Albanese C, Darnell JE (1999) Stat3 as an oncogene. Cell 98(3):295–303. doi:10.1016/s0092-8674(00)81959-5

    Article  CAS  PubMed  Google Scholar 

  19. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, Byrom D, Riera A, Rossell D, Mangues R, Massague J, Sancho E, Batlle E (2012) Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22(5):571–584. doi:10.1016/j.ccr.2012.08.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10(1):105–115. doi:10.1016/s1074-7613(00)80011-4

    Article  CAS  PubMed  Google Scholar 

  21. Chan E, Tan M, Xin J, Sudarsanam S, Johnson DE (2010) Interactions between traditional Chinese medicines and Western therapeutics. Curr Opin Drug Discov Devel 13(1):50–65

    CAS  PubMed  Google Scholar 

  22. Chan YK, Kwok HH, Chan LS, Leung KS, Shi J, Mak NK, Wong RN, Yue PY (2012) An indirubin derivative, E804, exhibits potent angiosuppressive activity. Biochem Pharmacol 83(5):598–607. doi:10.1016/j.bcp.2011.12.003

    Article  CAS  PubMed  Google Scholar 

  23. Cheng X, Alborzinia H, Merz KH, Steinbeisser H, Mrowka R, Scholl C, Kitanovic I, Eisenbrand G, Wolfl S (2012) Indirubin derivatives modulate TGFbeta/BMP signaling at different levels and trigger ubiquitin-mediated depletion of nonactivated R-Smads. Chem Biol 19(11):1423–1436. doi:10.1016/j.chembiol.2012.09.008

    Article  CAS  PubMed  Google Scholar 

  24. Cheng X, Dimou E, Alborzinia H, Wenke F, Gohring A, Reuter S, Mah N, Fuchs H, Andrade-Navarro MA, Adjaye J, Gul S, Harms C, Utikal J, Klipp E, Mrowka R, Wolfl S (2015) Identification of 2-[4-[(4-methoxyphenyl)methoxy]-phenyl]acetonitrile and derivatives as potent Oct3/4 inducers. J Med Chem 58(12):4976–4983. doi:10.1021/acs.jmedchem.5b00144

    Article  CAS  PubMed  Google Scholar 

  25. Cheng X, Holenya P, Can S, Alborzinia H, Rubbiani R, Ott I, Wolfl S (2014) A TrxR inhibiting gold(I) NHC complex induces apoptosis through ASK1-p38-MAPK signaling in pancreatic cancer cells. Mol Cancer 13(1):221. doi:10.1186/1476-4598-13-221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Cheng X, Kim JY, Ghafoory S, Duvaci T, Rafiee R, Theobald J, Alborzinia H, Holenya P, Fredebohm J, Merz K-H, Mehrabi A, Hafezi M, Saffari A, Eisenbrand G, Hoheisel JD, Wölfl S (2016) Methylisoindigo preferentially kills cancer stem cells by interfering cell metabolism via inhibition of LKB1 and activation of AMPK in PDACs. Mol Oncol. doi:10.1016/j.molonc.2016.01.008

    Google Scholar 

  27. Cheng X, Merz KH, Vatter S, Christ J, Wolfl S, Eisenbrand G (2014) 7,7′-diazaindirubin—a small molecule inhibitor of casein kinase 2 in vitro and in cells. Bioorg Med Chem 22(1):247–255. doi:10.1016/j.bmc.2013.11.031

    Article  CAS  PubMed  Google Scholar 

  28. Cheng X, Rasque P, Vatter S, Merz KH, Eisenbrand G (2010) Synthesis and cytotoxicity of novel indirubin-5-carboxamides. Bioorg Med Chem 18(12):4509–4515. doi:10.1016/j.bmc.2010.04.066

    Article  CAS  PubMed  Google Scholar 

  29. Cheng X, Yoshida H, Raoofi D, Saleh S, Alborzinia H, Wenke F, Gohring A, Reuter S, Mah N, Fuchs H, Andrade-Navarro MA, Adjaye J, Gul S, Utikal J, Mrowka R, Wolfl S (2015) Ethyl 2-((4-Chlorophenyl)amino)thiazole-4-carboxylate and derivatives are potent inducers of Oct3/4. J Med Chem 58(15):5742–5750. doi:10.1021/acs.jmedchem.5b00226

    Article  CAS  PubMed  Google Scholar 

  30. Choi SJ, Lee JE, Jeong SY, Im I, Lee SD, Lee EJ, Lee SK, Kwon SM, Ahn SG, Yoon JH, Han SY, Kim JI, Kim YC (2010) 5,5′-substituted indirubin-3′-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity. J Med Chem 53(9):3696–3706. doi:10.1021/jm100080z

    Article  CAS  PubMed  Google Scholar 

  31. Chou YF, Chen HH, Eijpe M, Yabuuchi A, Chenoweth JG, Tesar P, Lu J, McKay RD, Geijsen N (2008) The growth factor environment defines distinct pluripotent ground states in novel blastocyst-derived stem cells. Cell 135(3):449–461. doi:10.1016/j.cell.2008.08.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Clinical and experimental studies in the treatment of chronic granulocytic leukemia with indirubin (author’s transl) (1979). Zhonghua Nei Ke Za Zhi 18(2):83–88

    Google Scholar 

  33. Davey S (2015) 2015 Nobel Prize in physiology or medicine: punishing parasites. Nat Chem 7(12):949. doi:10.1038/nchem.2411

    Article  CAS  PubMed  Google Scholar 

  34. Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble ME (2001) Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate. Structure 9(5):389–397

    Article  CAS  PubMed  Google Scholar 

  35. Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334. doi:10.1146/annurev.pharmtox.43.100901.135828

    Article  CAS  PubMed  Google Scholar 

  36. Duensing S, Duensing A, Lee DC, Edwards KM, Piboonniyom SO, Manuel E, Skaltsounis L, Meijer L, Munger K (2004) Cyclin-dependent kinase inhibitor indirubin-3′-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies. Oncogene 23(50):8206–8215. doi:10.1038/sj.onc.1208012

    Article  CAS  PubMed  Google Scholar 

  37. Efferth T, Li PC, Konkimalla VS, Kaina B (2007) From traditional Chinese medicine to rational cancer therapy. Trends Mol Med 13(8):353–361. doi:10.1016/j.molmed.2007.07.001

    Article  CAS  PubMed  Google Scholar 

  38. Eisenbrand G, Cheng X, Zeller J, Merz K-H (2010) Impact of structural modifications on bioactivity and metabolic stability of indirubins. In: Proceedings of the American Association for cancer research annual meeting 51, pp 647–647

    Google Scholar 

  39. Eisenbrand G, Hippe F, Jakobs S, Muehlbeyer S (2004) Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine. J Cancer Res Clin Oncol 130(11):627–635. doi:10.1007/s00432-004-0579-2

    Article  CAS  PubMed  Google Scholar 

  40. Feng BZ (1984) [Sister chromatid exchange frequency of bone marrow cells and its response to indirubin in chronic myeloid leukemia]. Zhonghua Zhong Liu Za Zhi 6(5):357–360

    CAS  PubMed  Google Scholar 

  41. Feng BZ, Zhang YH, Qian LS, Chu YL (1984) [Effect of indirubin on SCE frequencies of BM cells in chronic myeloid leukemia]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 6(4):308–310

    CAS  PubMed  Google Scholar 

  42. Ferandin Y, Bettayeb K, Kritsanida M, Lozach O, Polychronopoulos P, Magiatis P, Skaltsounis AL, Meijer L (2006) 3′-Substituted 7-halogenoindirubins, a new class of cell death inducing agents. J Med Chem 49(15):4638–4649. doi:10.1021/jm060314i

    Article  CAS  PubMed  Google Scholar 

  43. Fuentealba LC, Eivers E, Ikeda A, Hurtado C, Kuroda H, Pera EM, De Robertis EM (2007) Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131(5):980–993. doi:10.1016/j.cell.2007.09.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fuxe J, Karlsson MC (2012) TGF-beta-induced epithelial-mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol 22(5–6):455–461. doi:10.1016/j.semcancer.2012.05.004

    Article  CAS  PubMed  Google Scholar 

  45. Gao X, Zhou Y, Wu KX, Ding YH, Fan DM, Yang M, Zhang YZ, Zhang YJ, Xiong DS (2015) Inhibitory effects of indirubin derivative PHII-7 on invasion and migration in metastatic cancer. Neoplasma 62(2):209–229. doi:10.4149/neo_2015_026

    Article  CAS  PubMed  Google Scholar 

  46. Ghafoory S, Mehrabi A, Hafezi M, Cheng X, Breitkopf-Heinlein K, Hick M, Huichalaf M, Herbel V, Saffari A, Wolfl S (2015) Nuclear accumulation of CDH1 mRNA in hepatocellular carcinoma cells. Oncogenesis 4:e152. doi:10.1038/oncsis.2015.11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE (2009) Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324(5935):1713–1716. doi:10.1126/science.1171721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. doi:10.1016/j.cell.2010.01.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Guengerich FP, Sorrells JL, Schmitt S, Krauser JA, Aryal P, Meijer L (2004) Generation of new protein kinase inhibitors utilizing cytochrome p450 mutant enzymes for indigoid synthesis. J Med Chem 47(12):3236–3241. doi:10.1021/jm030561b

    Article  CAS  PubMed  Google Scholar 

  50. Heshmati N, Cheng X, Dapat E, Sassene P, Eisenbrand G, Fricker G, Mullertz A (2014) In vitro and in vivo evaluations of the performance of an indirubin derivative, formulated in four different self-emulsifying drug delivery systems. J Pharm Pharmacol 66(11):1567–1575. doi:10.1111/jphp.12286

    Article  CAS  PubMed  Google Scholar 

  51. Heshmati N, Cheng X, Eisenbrand G, Fricker G (2013) Enhancement of oral bioavailability of E804 by self-nanoemulsifying drug delivery system (SNEDDS) in rats. J Pharm Sci 102(10):3792–3799. doi:10.1002/jps.23696

    Article  CAS  PubMed  Google Scholar 

  52. Heshmati N, Wagner B, Cheng X, Scholz T, Kansy M, Eisenbrand G, Fricker G (2013) Physicochemical characterization and in vitro permeation of an indirubin derivative. Eur J Pharm Sci 50(3–4):467–475. doi:10.1016/j.ejps.2013.08.021

    Article  CAS  PubMed  Google Scholar 

  53. Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L (1999) Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol 1(1):60–67. doi:10.1038/9035

    Article  CAS  PubMed  Google Scholar 

  54. Hu S, Cui W, Zhang Z, Mak S, Xu D, Li G, Hu Y, Wang Y, Lee M, Tsim KW, Han Y (2015) Indirubin-3-oxime effectively prevents 6OHDA-induced neurotoxicity in PC12 cells via activating MEF2D through the inhibition of GSK3beta. J Mol Neurosci 57(4):561–570. doi:10.1007/s12031-015-0638-y

    Article  CAS  PubMed  Google Scholar 

  55. Huang M, Lin HS, Lee YS, Ho PC (2014) Evaluation of meisoindigo, an indirubin derivative: in vitro antileukemic activity and in vivo pharmacokinetics. Int J Oncol 45(4):1724–1734. doi:10.3892/ijo.2014.2548

    CAS  PubMed  Google Scholar 

  56. Jautelat R, Brumby T, Schafer M, Briem H, Eisenbrand G, Schwahn S, Kruger M, Lucking U, Prien O, Siemeister G (2005) From the insoluble dye indirubin towards highly active, soluble CDK2-inhibitors. ChemBioChem 6(3):531–540. doi:10.1002/cbic.200400108

    Article  CAS  PubMed  Google Scholar 

  57. Ji XJ, Zhang FR (1985) [Studies on antineoplastic action of indirubin derivatives and analogs and their structure-activity relationships]. Yao Xue Xue Bao 20(2):137–139

    CAS  PubMed  Google Scholar 

  58. Ji XJ, Zhang FR, Lei JL, Xu YT (1981) [Studies on the antineoplastic action and toxicity of synthetic indirubin (author’s transl)]. Yao Xue Xue Bao 16(2):146–148

    CAS  PubMed  Google Scholar 

  59. Jung DW, Hong YJ, Kim SY, Kim WH, Seo S, Lee JE, Shen H, Kim YC, Williams DR (2014) 5-Nitro-5′hydroxy-indirubin-3′oxime is a novel inducer of somatic cell transdifferentiation. Arch Pharm (Weinheim) 347(11):806–818. doi:10.1002/ardp.201400223

    Article  CAS  Google Scholar 

  60. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092):431–436. doi:10.1038/nature04870

    Article  CAS  PubMed  Google Scholar 

  61. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10):749–759. doi:10.1038/nri1703

    Article  CAS  PubMed  Google Scholar 

  62. Kim EJ, Park WH, Ahn SG, Yoon JH, Kim SW, Kim SA (2010) 5′-nitro-indirubinoxime inhibits inflammatory response in TNF-alpha stimulated human umbilical vein endothelial cells. Atherosclerosis 211(1):77–83. doi:10.1016/j.atherosclerosis.2010.01.040

    Article  CAS  PubMed  Google Scholar 

  63. Kim JK, Park GM (2012) Indirubin-3-monoxime exhibits anti-inflammatory properties by down-regulating NF-kappaB and JNK signaling pathways in lipopolysaccharide-treated RAW264.7 cells. Inflamm Res Off J Eur Histamine Res Soc 61(4):319–325. doi:10.1007/s00011-011-0413-7

    Google Scholar 

  64. Kim MH, Choi YY, Yang G, Cho IH, Nam D, Yang WM (2013) Indirubin, a purple 3,2- bisindole, inhibited allergic contact dermatitis via regulating T helper (Th)-mediated immune system in DNCB-induced model. J Ethnopharmacol 145(1):214–219. doi:10.1016/j.jep.2012.10.055

    Article  CAS  PubMed  Google Scholar 

  65. Kim SH, Kim SW, Choi SJ, Kim YC, Kim TS (2006) Enhancing effect of indirubin derivatives on 1,25-dihydroxyvitamin D3- and all-trans retinoic acid-induced differentiation of HL-60 leukemia cells. Bioorg Med Chem 14(19):6752–6758. doi:10.1016/j.bmc.2006.05.044

    Article  CAS  PubMed  Google Scholar 

  66. Knockaert M, Blondel M, Bach S, Leost M, Elbi C, Hager GL, Nagy SR, Han D, Denison M, Ffrench M, Ryan XP, Magiatis P, Polychronopoulos P, Greengard P, Skaltsounis L, Meijer L (2004) Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins. Oncogene 23(25):4400–4412. doi:10.1038/sj.onc.1207535

    Article  CAS  PubMed  Google Scholar 

  67. Kritsanida M, Magiatis P, Skaltsounis AL, Peng Y, Li P, Wennogle LP (2009) Synthesis and antiproliferative activity of 7-azaindirubin-3′-oxime, a 7-aza isostere of the natural indirubin pharmacophore. J Nat Prod 72(12):2199–2202. doi:10.1021/np9003905

    Article  CAS  PubMed  Google Scholar 

  68. Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L (2001) Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 276(1):251–260. doi:10.1074/jbc.M002466200

    Article  CAS  PubMed  Google Scholar 

  69. Lee JW, Moon MJ, Min HY, Chung HJ, Park EJ, Park HJ, Hong JY, Kim YC, Lee SK (2005) Induction of apoptosis by a novel indirubin-5-nitro-3′-monoxime, a CDK inhibitor, in human lung cancer cells. Bioorg Med Chem Lett 15(17):3948–3952. doi:10.1016/j.bmcl.2005.05.105

    Article  CAS  PubMed  Google Scholar 

  70. Lee MY, Liu YW, Chen MH, Wu JY, Ho HY, Wang QF, Chuang JJ (2013) Indirubin-3′-monoxime promotes autophagic and apoptotic death in JM1 human acute lymphoblastic leukemia cells and K562 human chronic myelogenous leukemia cells. Oncol Rep 29(5):2072–2078. doi:10.3892/or.2013.2334

    CAS  PubMed  Google Scholar 

  71. Liao XM, Leung KN (2013) Indirubin-3′-oxime induces mitochondrial dysfunction and triggers growth inhibition and cell cycle arrest in human neuroblastoma cells. Oncol Rep 29(1):371–379. doi:10.3892/or.2012.2094

    CAS  PubMed  Google Scholar 

  72. Libnow S, Methling K, Hein M, Michalik D, Harms M, Wende K, Flemming A, Kockerling M, Reinke H, Bednarski PJ, Lalk M, Langer P (2008) Synthesis of indirubin-N′-glycosides and their anti-proliferative activity against human cancer cell lines. Bioorg Med Chem 16(10):5570–5583. doi:10.1016/j.bmc.2008.04.003

    Article  CAS  PubMed  Google Scholar 

  73. Liu XP, Sun H, Qi J, Wang LL, He SW, Liu J, Feng CQ, Chen CL, Li W, Guo YQ, Qin DJ, Pan GJ, Chen JK, Pei DQ, Zheng H (2013) Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat Cell Biol 15(7):829–838. doi:10.1038/Ncb2765

    Article  CAS  PubMed  Google Scholar 

  74. Lo WY, Chang NW (2013) An indirubin derivative, indirubin-3′-monoxime suppresses oral cancer tumorigenesis through the downregulation of survivin. PLoS ONE 8(8):e70198. doi:10.1371/journal.pone.0070198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi:10.1038/nature07205

    Article  CAS  PubMed  Google Scholar 

  76. Marko D, Schatzle S, Friedel A, Genzlinger A, Zankl H, Meijer L, Eisenbrand G (2001) Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer 84(2):283–289. doi:10.1054/bjoc.2000.1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Martinet J, Dornier O (1921) On the new sulfonated derivatives of oxindol and of isatin. Cr Hebd Acad Sci 172:1415–1417

    CAS  Google Scholar 

  78. Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R, Crovace C, Tarricone C, Musacchio A, Roe SM, Pearl L, Greengard P (2003) GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem Biol 10(12):1255–1266

    Article  CAS  PubMed  Google Scholar 

  79. Merz K-H, Eisenbrand G (2006) Chemistry and structure-activity of indirubins. In: Meijer L, Guyard N, Skaltsounis L, Eisenbrand G (eds) Indirubin, the red shade of indigo. Editions ‘Life in progress’, Roscoff, pp 203–208

    Google Scholar 

  80. Merz KH, Schwahn S, Hippe F, Muhlbeyer S, Jakobs S, Eisenbrand G (2004) Novel indirubin derivatives, promising anti-tumor agents inhibiting cyclin-dependent kinases. Int J Clin Pharmacol Ther 42(11):656–658

    Article  CAS  PubMed  Google Scholar 

  81. Miller LH, Su X (2011) Artemisinin: discovery from the Chinese herbal garden. Cell 146(6):855–858. doi:10.1016/j.cell.2011.08.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Miyoshi K, Takaishi M, Digiovanni J, Sano S (2012) Attenuation of psoriasis-like skin lesion in a mouse model by topical treatment with indirubin and its derivative E804. J Dermatol Sci 65(1):70–72. doi:10.1016/j.jdermsci.2011.10.001

    Article  CAS  PubMed  Google Scholar 

  83. Mok CK, Kang SS, Chan RW, Yue PY, Mak NK, Poon LL, Wong RN, Peiris JS, Chan MC (2014) Anti-inflammatory and antiviral effects of indirubin derivatives in influenza A (H5N1) virus infected primary human peripheral blood-derived macrophages and alveolar epithelial cells. Antiviral Res 106:95–104. doi:10.1016/j.antiviral.2014.03.019

    Article  CAS  PubMed  Google Scholar 

  84. Moon MJ, Lee SK, Lee JW, Song WK, Kim SW, Kim JI, Cho C, Choi SJ, Kim YC (2006) Synthesis and structure-activity relationships of novel indirubin derivatives as potent anti-proliferative agents with CDK2 inhibitory activities. Bioorg Med Chem 14(1):237–246. doi:10.1016/j.bmc.2005.08.008

    Article  CAS  PubMed  Google Scholar 

  85. Myrianthopoulos V, Kritsanida M, Gaboriaud-Kolar N, Magiatis P, Ferandin Y, Durieu E, Lozach O, Cappel D, Soundararajan M, Filippakopoulos P, Sherman W, Knapp S, Meijer L, Mikros E, Skaltsounis AL (2013) Novel inverse binding mode of indirubin derivatives yields improved selectivity for DYRK kinases. ACS Med Chem Lett 4(1):22–26. doi:10.1021/ml300207a

    Article  CAS  PubMed  Google Scholar 

  86. Myrianthopoulos V, Magiatis P, Ferandin Y, Skaltsounis AL, Meijer L, Mikros E (2007) An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted indirubins. J Med Chem 50(17):4027–4037. doi:10.1021/jm070077z

    Article  CAS  PubMed  Google Scholar 

  87. Nam S, Buettner R, Turkson J, Kim D, Cheng JQ, Muehlbeyer S, Hippe F, Vatter S, Merz KH, Eisenbrand G, Jove R (2005) Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells. Proc Natl Acad Sci USA 102(17):5998–6003. doi:10.1073/pnas.0409467102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Nam S, Scuto A, Yang F, Chen W, Park S, Yoo HS, Konig H, Bhatia R, Cheng X, Merz KH, Eisenbrand G, Jove R (2012) Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol Oncol 6(3):276–283. doi:10.1016/j.molonc.2012.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nam S, Wen W, Schroeder A, Herrmann A, Yu H, Cheng X, Merz KH, Eisenbrand G, Li H, Yuan YC, Jove R (2013) Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells. Mol Oncol 7(3):369–378. doi:10.1016/j.molonc.2012.10.013

    Article  CAS  PubMed  Google Scholar 

  90. Noble ME, Endicott JA, Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science 303(5665):1800–1805. doi:10.1126/science.1095920

    Article  CAS  PubMed  Google Scholar 

  91. Pandraud H (1961) Structure Cristalline De Lindirubine. Acta Crystallogr 14(9):901. doi:10.1107/S0365110x61002667

    Article  Google Scholar 

  92. Park EJ, Choi SJ, Kim YC, Lee SH, Park SW, Lee SK (2009) Novel small molecule activators of beta-catenin-mediated signaling pathway: structure-activity relationships of indirubins. Bioorg Med Chem Lett 19(8):2282–2284. doi:10.1016/j.bmcl.2009.02.083

    Article  CAS  PubMed  Google Scholar 

  93. Pergola C, Gaboriaud-Kolar N, Jestadt N, Konig S, Kritsanida M, Schaible AM, Li H, Garscha U, Weinigel C, Barz D, Albring KF, Huber O, Skaltsounis AL, Werz O (2014) Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase. J Med Chem 57(9):3715–3723. doi:10.1021/jm401740w

    Article  CAS  PubMed  Google Scholar 

  94. Polychronopoulos P, Magiatis P, Skaltsounis AL, Myrianthopoulos V, Mikros E, Tarricone A, Musacchio A, Roe SM, Pearl L, Leost M, Greengard P, Meijer L (2004) Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J Med Chem 47(4):935–946. doi:10.1021/jm031016d

    Article  CAS  PubMed  Google Scholar 

  95. Prochazkova J, Kozubik A, Machala M, Vondracek J (2011) Differential effects of indirubin and 2,3,7,8-tetrachlorodibenzo-p-dioxin on the aryl hydrocarbon receptor (AhR) signalling in liver progenitor cells. Toxicology 279(1–3):146–154. doi:10.1016/j.tox.2010.10.003

    Article  CAS  PubMed  Google Scholar 

  96. Rahman SH, Bobis-Wozowicz S, Chatterjee D, Gellhaus K, Pars K, Heilbronn R, Jacobs R, Cathomen T (2013) The nontoxic cell cycle modulator indirubin augments transduction of adeno-associated viral vectors and zinc-finger nuclease-mediated gene targeting. Hum Gene Ther 24(1):67–77. doi:10.1089/hum.2012.168

    Article  CAS  PubMed  Google Scholar 

  97. Ribas J, Bettayeb K, Ferandin Y, Knockaert M, Garrofe-Ochoa X, Totzke F, Schachtele C, Mester J, Polychronopoulos P, Magiatis P, Skaltsounis AL, Boix J, Meijer L (2006) 7-Bromoindirubin-3′-oxime induces caspase-independent cell death. Oncogene 25(47):6304–6318. doi:10.1038/sj.onc.1209648

    Article  CAS  PubMed  Google Scholar 

  98. Russell GA, Kaupp G (1969) Oxidation of carbanions. 4. Oxidation of indoxyl to indigo in basic solution. J A Chem Soc 91(14):3851. doi:10.1021/ja01042a028

    Article  CAS  Google Scholar 

  99. Saito H, Tabata K, Hanada S, Kanda Y, Suzuki T, Miyairi S (2011) Synthesis of methoxy- and bromo-substituted indirubins and their activities on apoptosis induction in human neuroblastoma cells. Bioorg Med Chem Lett 21(18):5370–5373. doi:10.1016/j.bmcl.2011.07.011

    Article  CAS  PubMed  Google Scholar 

  100. Sapkota G, Alarcon C, Spagnoli FM, Brivanlou AH, Massague J (2007) Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell 25(3):441–454. doi:10.1016/j.molcel.2007.01.006

    Article  CAS  PubMed  Google Scholar 

  101. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10(1):55–63. doi:10.1038/nm979

    Article  CAS  PubMed  Google Scholar 

  102. Sethi G, Ahn KS, Sandur SK, Lin X, Chaturvedi MM, Aggarwal BB (2006) Indirubin enhances tumor necrosis factor-induced apoptosis through modulation of nuclear factor-kappa B signaling pathway. J Biol Chem 281(33):23425–23435. doi:10.1074/jbc.M602627200

    Article  CAS  PubMed  Google Scholar 

  103. Sharma S, Taliyan R (2014) Neuroprotective role of Indirubin-3′-monoxime, a GSKbeta inhibitor in high fat diet induced cognitive impairment in mice. Biochem Biophys Res Commun 452(4):1009–1015. doi:10.1016/j.bbrc.2014.09.034

    Article  CAS  PubMed  Google Scholar 

  104. Shin EK, Kim JK (2012) Indirubin derivative E804 inhibits angiogenesis. BMC Cancer 12:164. doi:10.1186/1471-2407-12-164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Smyth LA, Matthews TP, Collins I (2011) Design and evaluation of 3-aminopyrazolopyridinone kinase inhibitors inspired by the natural product indirubin. Bioorg Med Chem 19(11):3569–3578. doi:10.1016/j.bmc.2011.03.069

    Article  CAS  PubMed  Google Scholar 

  106. Song JH, Lee JE, Cho KM, Park SH, Kim HJ, Kim YC, Kim TS (2015) 5-diphenylacetamido-indirubin-3′-oxime as a novel mitochondria-targeting agent with anti-leukemic activities. Mol Carcinog. doi:10.1002/mc.22307

    Google Scholar 

  107. Spink BC, Hussain MM, Katz BH, Eisele L, Spink DC (2003) Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin. Biochem Pharmacol 66(12):2313–2321

    Article  CAS  PubMed  Google Scholar 

  108. Stockinger B, Di Meglio P, Gialitakis M, Duarte JH (2014) The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32:403–432. doi:10.1146/annurev-immunol-032713-120245

    Article  CAS  PubMed  Google Scholar 

  109. Sugihara K, Kitamura S, Yamada T, Okayama T, Ohta S, Yamashita K, Yasuda M, Fujii-Kuriyama Y, Saeki K, Matsui S, Matsuda T (2004) Aryl hydrocarbon receptor-mediated induction of microsomal drug-metabolizing enzyme activity by indirubin and indigo. Biochem Biophys Res Commun 318(2):571–578. doi:10.1016/j.bbrc.2004.04.066

    Article  CAS  PubMed  Google Scholar 

  110. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. P Natl Acad Sci USA 94(8):3801–3804. doi:10.1073/pnas.94.8.3801

    Article  CAS  Google Scholar 

  111. Tanaka T, Ohashi S, Saito H, Higuchi T, Tabata K, Kosuge Y, Suzuki T, Miyairi S, Kobayashi S (2014) Indirubin derivatives alter DNA binding activity of the transcription factor NF-Y and inhibit MDR1 gene promoter. Eur J Pharmacol 741:83–89. doi:10.1016/j.ejphar.2014.07.035

    Article  CAS  PubMed  Google Scholar 

  112. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  113. Tu Y (2011) The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med 17(10):1217–1220. doi:10.1038/nm.2471

    Article  CAS  PubMed  Google Scholar 

  114. Udumula MP, Medapi B, Dhar I, Bhat A, Desai K, Sriram D, Dhar A (2015) The small molecule indirubin-3′-oxime inhibits protein kinase R: antiapoptotic and antioxidant effect in rat cardiac myocytes. Pharmacology 97(1–2):25–30. doi:10.1159/000441727

    Article  PubMed  CAS  Google Scholar 

  115. Vougogiannopoulou K, Ferandin Y, Bettayeb K, Myrianthopoulos V, Lozach O, Fan Y, Johnson CH, Magiatis P, Skaltsounis AL, Mikros E, Meijer L (2008) Soluble 3′,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase-3 alter circadian period. J Med Chem 51(20):6421–6431. doi:10.1021/jm800648y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wan JH, You YC, Mi JX, Ying HG (1981) [Effect of indirubin on hemopoietic cell production (author’s transl)]. Zhongguo Yao Li Xue Bao 2(4):241–244

    CAS  PubMed  Google Scholar 

  117. Wang L, Li X, Liu X, Lu K, Chen NA, Li P, Lv X, Wang X (2015) Enhancing effects of indirubin on the arsenic disulfide-induced apoptosis of human diffuse large B-cell lymphoma cells. Oncol Lett 9(4):1940–1946. doi:10.3892/ol.2015.2941

    PubMed  PubMed Central  Google Scholar 

  118. Wang Y, Hoi PM, Chan JY, Lee SM (2014) New perspective on the dual functions of indirubins in cancer therapy and neuroprotection. Anticancer Agents Med Chem 14(9):1213–1219

    Article  CAS  PubMed  Google Scholar 

  119. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323(5915):793–797. doi:10.1126/science.1164551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wen Z, Zhong Z, Darnell JE Jr (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82(2):241–250

    Article  CAS  PubMed  Google Scholar 

  121. Wongsaroj L, Sallabhan R, Dubbs JM, Mongkolsuk S, Loprasert S (2015) Cloning of toluene 4-monooxygenase genes and application of two-phase system to the production of the anticancer agent, indirubin. Mol Biotechnol 57(8):720–726. doi:10.1007/s12033-015-9863-4

    Article  CAS  PubMed  Google Scholar 

  122. Wu GY, Fang FD (1980) [Studies on the mechanism of indirubin action in the treatment of chronic granulocytic leukemia. II. Effects of indirubin on nucleic acid and protein synthesis in animal transplantable tumor cells and normal proliferating cells in vitro (author’s transl)]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2(2):83–87

    CAS  PubMed  Google Scholar 

  123. Wu GY, Liu JZ, Fang FD, Zuo J (1982) Studies on the mechanism of indirubin action in the treatment of chronic granulocytic leukemia. V. Binding between indirubin and DNA and identification of the type of binding. Sci Sin B 25(10):1071–1079

    Google Scholar 

  124. Xiao Z, Hao Y (2006) From Danggui Longhui Wang to meisoindigo: experience in the treatment of chronic myelogenous leukemia in China. In: Meijer L, Guyard N, Skaltsounis L, Eisenbrand, G (eds) Indirubin, the red shade of indigo. Editions ‘Life in progress’, Roscoff, pp 203–208

    Google Scholar 

  125. Xiao Z, Hao Y, Liu B, Qian L (2002) Indirubin and meisoindigo in the treatment of chronic myelogenous leukemia in China. Leukemia Lymphoma 43(9):1763–1768. doi:10.1080/1042819021000006295

    Article  CAS  PubMed  Google Scholar 

  126. Yu CL, Meyer DJ, Campbell GS, Larner AC, Cartersu C, Schwartz J, Jove R (1995) Enhanced DNA-binding activity of a STAT3-related protein in cells transformed by the SRC oncoprotein. Science 269(5220):81–83. doi:10.1126/science.7541555

    Article  CAS  PubMed  Google Scholar 

  127. Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14(11):736–746. doi:10.1038/nrc3818

    Article  CAS  PubMed  Google Scholar 

  128. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809. doi:10.1038/nrc2734 (nrc2734 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yuan ZZ, Sun DT (1987) [Clinical and ultrastructural study on psoriasis treated by indirubin]. Zhonghua Yi Xue Za Zhi 67(1):7–8

    CAS  PubMed  Google Scholar 

  130. Zahoor M, Cha PH, Choi KY (2014) Indirubin-3′-oxime, an activator of Wnt/beta-catenin signaling, enhances osteogenic commitment of ST2 cells and restores bone loss in high-fat diet-induced obese male mice. Bone 65:60–68. doi:10.1016/j.bone.2014.05.003

    Article  CAS  PubMed  Google Scholar 

  131. Zahoor M, Cha PH, Min do S, Choi KY (2014b) Indirubin-3′-oxime reverses bone loss in ovariectomized and hindlimb-unloaded mice via activation of the Wnt/beta-catenin signaling. J Bone Miner Res 29 (5):1196–1205. doi:10.1002/jbmr.2147

    Google Scholar 

  132. Zhang X, Song Y, Wu Y, Dong Y, Lai L, Zhang J, Lu B, Dai F, He L, Liu M, Yi Z (2011) Indirubin inhibits tumor growth by antitumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell. Int J Cancer 129(10):2502–2511. doi:10.1002/ijc.25909

    Article  CAS  PubMed  Google Scholar 

  133. Zhao PP (1981) [Determination of indirubin by dual wavelength TLC scanner (author’s transl)]. Zhong Yao Tong Bao 6(4):28–30

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Gerhard Eisenbrand and Stefan Wölfl for their great supporting. This work is supported by the BMBF grant programs SysToxChip 031A202E. We apologize that we were unable to cite all related primary research papers and excellent reviews due to space limitations.

Author information

Authors and Affiliations

  1. Institute of Pharmacy and Molecular Biotechnology, Pharmaceutical Biology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany

    Xinlai Cheng

  2. Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Str. 52, 67663, Kaiserslautern, Germany

    Karl-Heinz Merz

Authors
  1. Xinlai Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karl-Heinz Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xinlai Cheng .

Editor information

Editors and Affiliations

  1. Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Subash Chandra Gupta

  2. MD Anderson Cancer Center, University of Texas, Houston, Texas, USA

    Sahdeo Prasad

  3. Inflammation Research Institute, San Diego, California, USA

    Bharat B. Aggarwal

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Cheng, X., Merz, KH. (2016). The Role of Indirubins in Inflammation and Associated Tumorigenesis. In: Gupta, S., Prasad, S., Aggarwal, B. (eds) Drug Discovery from Mother Nature. Advances in Experimental Medicine and Biology, vol 929. Springer, Cham. https://doi.org/10.1007/978-3-319-41342-6_12

Download citation

Publish with us

Policies and ethics

Search

Navigation