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Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.11.2004 | Review

Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine

verfasst von: Gerhard Eisenbrand, Frankie Hippe, Sandra Jakobs, Stephan Muehlbeyer

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 11/2004

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Abstract

Indirubin, a 3, 2’ bisindole isomer of indigo, has originally been identified as the active principle of a traditional Chinese preparation and has been proven to exhibit antileukemic effectiveness in chronic myelocytic leukemia. Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site. This seminal finding triggered our research to improve the pharmacological activities of the parent molecule within comprehensive structure-activity studies. Molecular modifications made novel anticancer compounds accessible with strongly improved CDK inhibitory potential and with broad spectrum antitumour activity. This novel family of compounds holds strong promise for clinical anticancer activity and might be useful also in several important noncancer indications, including Alzheimer’s disease or diabetes.

Bernards R (1997) E2F: a nodal point in cell cycle regulation. Biochim Biophys Acta 1333:M33–M40

Carnero A and Hannon GJ (1997) The INK4 family of CDK inhibitors. In: Vogt PK and Reed SI (eds) Cyclin-dependent kinase (CDK) inhibitors, 1st edn. Springer, Berlin Hidleberg New York, pp 43–56

Chang HM, But PPH (1996) Pharmacology and applications of Chinese materia medica, vol. 2. World Scientific, Singapore

Cheng MP, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ (1999) The p21(Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclinD-dependent kinases in murine fibroblasts. EMBO J 18:1571–1583CrossRefPubMed

Cohen P (1999) The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction. Philos Trans R Soc Lond B Biol Sci 354:485–495CrossRefPubMed

Coleman KG, Lyssikatos JP, Yang BV (1997) Chemical inhibitors of cyclin-dependent kinases. Ann Rep Med Chem 32:171–179

Connell-Crowley L, Harper JW, Goodrich DW (1997) CycinD1/CDK4 regulates retinoblastoma protein mediated cell cycle arrest by specific phosphorylation. Mol Biol Cell 8:287–301PubMed

Damiens E, Baratte B, Marie D, Eisenbrand G, Meijer L (2001) Anti-mitotic properties of indirubin-3’-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest. Oncogene 20:3786–3797CrossRefPubMed

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, 9:389–397

Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998) Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12:3499–3511PubMed

Draetta G, Pagano M (1996) Cell cycle control and cancer. Ann Rep Med Chem 31:241–248

Du D, Ceng Q (1981) Effect of indirubin on the incorporation of isotope labeled precursors into nucleic acid and protein of tumour tissues. Zhongcaoya 12:406–409

Edamatsu H, Gau CL, Nemoto T, Guo L, Tamanoi F (2000) CDK inhibitors, roscovitine and olomoucine, synergize with farnesyl transferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines. Oncogene 19:3059–3068CrossRefPubMed

Eisenbrand G, Muehlbeyer S, Hippe F, Jakobs S (2004) Novel indirubin derivatives, promising anti-tumor agents. AACR, 95th annual meeting, Orlando, FL, USA

Emily-Fenouil F, Ghiglione C, Lhomond G, Lepage T, Gache C (1998) GSK3beta/shaggy mediates patterning along the animal-vegetal axis of the sea urchin embryo. Development 125:89–98

Fiebig HH, Marko D, Eisenbrand G (2001) Indirubins, novel potent inhibitors of cyclin-dependent kinases, inhibit the growth of human xenograft tumours. AACR, 92nd annual meeting, New Orleans, LA, USA

Gan WJ, Yang T, Wen S, Liu Y, Tan Z, Deng C, Wu J, Liu M (1985) Studies on the mechanism of indirubin action in the treatment of chronic myelocytic leukemia (CML). II. 5’-Nucleotidase in the peripheral white blood cells of CML. Chin Acad Med Sci Beijing 6:611–613

Garrett MD, Fattaey A (1999) CDK inhibition and cancer therapy. Curr Opin Genet Dev 9:104–111CrossRefPubMed

Gray N, Detivaud L, Doerig C, Meijer L (1999) ATP-site directed inhibitors of cyclin-dependent kinases. Curr Med Chem 6:859–875PubMed

Han R (1994) Highlight on the studies of anticancer drugs derived from plants in China. Stem Cells 12:53–63PubMed

Harbour JW, Dean DC (2000) Rb function in cell-cycle regulation and apoptosis. Nature Cell Biol 2:E65–E67CrossRefPubMed

He X, Saint-Jeannet JP, Woodgett HE, Varmus HE, Dawid IB (1995) Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature 374:617–22CrossRefPubMed

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 1:60–67PubMed

Imahori K, Uchida T (1997) Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. J Biochem (Tokyo) 121:179–88

Ji XJ, Zhang FR, Lei JL, Xu YT (1981) Studies on the antineoplastic effect and toxicity of synthetic indirubin. Yaoxue Xuebao 16:146–148

LaBaer MD, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E (1997) New functional activities for the p21 family of CDK inhibitors. Genes Dev 11:847–862PubMed

Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow E-M, Eisenbrand G, Meijer L (2001) Indirubins inhibit glycogen synthase kinase-3β and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in alzheimer’s disease. J Biol Chem 276:251–260CrossRefPubMed

Lee JC, Adams JL (1995) Inhibitors of serine/threonine kinases. Curr Opin Biotech 6:657–661CrossRefPubMed

Lee K, Shih CY, Yang TY, Chien LS, Chao WM, Sun CS, Wang TC, Pien SK, Sung KH (1979) Ultrastructural study on the mechanism of the therapeutic effect of indirubin for human chronic granulocytic leukemia. Zhinghua Yixue Zazhi 59:129–132

Li Q (1987) The chemical constituents of Qing Dai. Zhiwu Xuebao 29:67–72

Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1:222–231CrossRefPubMed

Mandelkow EM, Mandelkow E (1998) Tau in Alzheimer’s disease. Trends Cell Biol 8:425–427CrossRefPubMed

Marko D, Schätzle 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 84:283–289CrossRefPubMed

Meijer L (1996) Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol 6:393–397CrossRefPubMed

Morgan DO (1997) Cyclin- dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291CrossRefPubMed

Mueller H, Helin K (2000) The E2F transcription factors: key regulators of cell proliferation. Biochim Biophys Acta 1470:M1–M12

Senderowicz AM, Sausville EA (2000) Preclinical and clinical development of CDK modulators. J Natl Cancer Inst 92:376–387CrossRefPubMed

Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163PubMed

Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512PubMed

Sielecki TM, Boylan JF, Benfield PA, Trainor GL (2000) Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. J Med Chem 43:1–18CrossRef

Soni R, O’Reilly T, Furet P, Muller L, Stephan C, Zumstein-Mecker S, Fretz H, Fabbro D, Chaudhuri B (2001) Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4. J Natl Cancer Inst 93:436–446CrossRefPubMed

Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE, Birmbaum MJ (1999) The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. J Biol Chem 274:17934–17940CrossRefPubMed

Tamrakar S, Rubin E, Ludlow JW (2000) Role of pRb dephosphorylation in cell cycle regulation. Front Biosci 5:121–137

Tang W, Eisenbrand G (1992) Chinese drugs of plant origin: chemistry, pharmacology, and use in traditional and modern medicine. Springer, Berlin Heidelberg New York

Toledo LM, Lydon NB, Elbaum D (1999) Structure-based design of ATP-site directed protein kinase inhibitors. Curr Med Chem 6:775–805PubMed

Toogood PL (2001) Cyclin-dependent kinase inhibitors for treating cancer. Med Res Rev 21:487–498CrossRefPubMed

Van den Heuvel S, Harlow E (1993) Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262:2050–2054PubMed

Walker DH (1998) Small molecule inhibitors of cyclin-dependent kinases: molecular tools and potential therapeutics. Curr Top Microbiol Immunol 227:149–165PubMed

Wan JH, You YC, Mi JX, Ying HG (1981) Effect of indirubin on hematopoietic cell production. Acta Pharmacol Sin 2:241–244

Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81:323–330PubMed

Willert K, Nusse R (1998) Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 8:95–102CrossRefPubMed

Wu GY, Fang FD, Liu JZ, Chang A, Ho YH (1980) Studies on the mechanism of action of indirubin in the treatment of chronic granulocytic leukemia. I. Effects on nucleic acid and protein synthesis in human leukemic cells. Chinese Med J 60:451–454

Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT (1996) The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev 10:1443–1454PubMed

Zhang S (1983) Studies on the chemical constituents of Isatis indigotica root. Chinese Trad Herb Drugs 14:247–248

Zhang ZN, Liu EK, Zheng TL, Li DG (1985) Treatment of chronic myelocytic leukemia (CML) by traditional Chinese medicine and Western medicine alternatively. J Trad Chinese Med 5:246–248

Zheng QT, Lu DJ, Yang SL (1979a) Pharmalogical studies of indirubin. I. Antitumor effect. Comm Chinese Herb Med 10:35–39

Zheng QT, Qi SB, Cheng ZY (1979b) Pharmacological studies of indirubin. II. Absorption, distribution and excretion of ³H-indirubin. Comm Chinese Herb Med 10:19–21

Titel: Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine
verfasst von: Gerhard Eisenbrand
Frankie Hippe
Sandra Jakobs
Stephan Muehlbeyer
Publikationsdatum: 01.11.2004
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 11/2004
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-004-0579-2

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