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

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.

[1]  P. Toogood.  Cyclin‐dependent kinase inhibitors for treating cancer , 2001, Medicinal research reviews.

[2]  Zhang Zn,et al.  Treatment of chronic myelocytic leukemia (CML) by traditional Chinese medicine and Western medicine alternately. , 1985 .

[3]  J. Harbour,et al.  Rb function in cell-cycle regulation and apoptosis , 2000, Nature Cell Biology.

[4]  P. May,et al.  Cell cycle control and cancer. , 2000, Pathologie-biologie.

[5]  R. Bernards,et al.  E2F: a nodal point in cell cycle regulation. , 1997, Biochimica et biophysica acta.

[6]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[7]  G Eisenbrand,et al.  Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulphonate. , 2001, Structure.

[8]  L. Meijer,et al.  ATP-site directed inhibitors of cyclin-dependent kinases. , 1999, Current medicinal chemistry.

[9]  R. Moon,et al.  The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. , 1996, Genes & development.

[10]  S. van den Heuvel,et al.  Distinct roles for cyclin-dependent kinases in cell cycle control. , 1993, Science.

[11]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[12]  K. Imahori,et al.  Physiology and pathology of tau protein kinases in relation to Alzheimer's disease. , 1997, Journal of biochemistry.

[13]  G L Snyder,et al.  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? , 2001, The Journal of biological chemistry.

[14]  M. Pagano,et al.  Chapter 25. Cell Cycle Control and Cancer , 1996 .

[15]  J. Adams,et al.  Inhibitors of serine/threonine kinases. , 1995, Current opinion in biotechnology.

[16]  L. Toledo,et al.  The structure-based design of ATP-site directed protein kinase inhibitors. , 1999, Current medicinal chemistry.

[17]  E. Rubin,et al.  Role of pRB dephosphorylation in cell cycle regulation. , 2000, Frontiers in bioscience : a journal and virtual library.

[18]  L. Meijer,et al.  Anti-mitotic properties of indirubin-3′-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest , 2001, Oncogene.

[19]  R. Nusse,et al.  β-catenin: a key mediator of Wnt signaling , 1998 .

[20]  E. Mandelkow,et al.  Tau in Alzheimer's disease. , 1998, Trends in cell biology.

[21]  Harold E. Varmus,et al.  Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos , 1995, Nature.

[22]  K. Coleman,et al.  Chapter 17. Chemical Inhibitors of Cyclin-dependent Kinases , 1997 .

[23]  A. Fattaey,et al.  CDK inhibition and cancer therapy. , 1999, Current opinion in genetics & development.

[24]  K. Helin,et al.  The E2F transcription factors: key regulators of cell proliferation. , 2000, Biochimica et biophysica acta.

[25]  Gerhard Eisenbrand,et al.  Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine , 1992 .

[26]  T. Lepage,et al.  GSK3beta/shaggy mediates patterning along the animal-vegetal axis of the sea urchin embryo. , 1998, Development.

[27]  Wu Gy,et al.  [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)]. , 1980 .

[28]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[29]  Li Qing-hua.  The Chemical Constituents of Qing Dai , 1987 .

[30]  P. But,et al.  Pharmacology and applications of chinese materia medica , 1986 .

[31]  M. Roussel,et al.  Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. , 1998, Genes & development.

[32]  G. Eisenbrand,et al.  Novel indirubin derivatives, promising anti-tumor agents inhibiting cyclin-dependent kinases. , 2004, International journal of clinical pharmacology and therapeutics.

[33]  K Willert,et al.  Beta-catenin: a key mediator of Wnt signaling. , 1998, Current opinion in genetics & development.

[34]  James M. Roberts,et al.  The p21Cip1 and p27Kip1 CDK ‘inhibitors’ are essential activators of cyclin D‐dependent kinases in murine fibroblasts , 1999, The EMBO journal.

[35]  J. LaBaer,et al.  New functional activities for the p21 family of CDK inhibitors. , 1997, Genes & development.

[36]  D O Morgan,et al.  Cyclin-dependent kinases: engines, clocks, and microprocessors. , 1997, Annual review of cell and developmental biology.

[37]  D. Fabbro,et al.  Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4. , 2001, Journal of the National Cancer Institute.

[38]  E. Sausville,et al.  Preclinical and clinical development of cyclin-dependent kinase modulators. , 2000, Journal of the National Cancer Institute.

[39]  M. Barbacid,et al.  To cycle or not to cycle: a critical decision in cancer , 2001, Nature reviews. Cancer.

[40]  Doris Marko,et al.  Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases , 1999, Nature Cell Biology.

[41]  G L Trainor,et al.  Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. , 2000, Journal of medicinal chemistry.

[42]  Xu Han.  Studies on the chemical constituents of Isatis indigotica in root , 2003 .

[43]  R A Roth,et al.  The Role of Glycogen Synthase Kinase 3β in Insulin-stimulated Glucose Metabolism* , 1999, The Journal of Biological Chemistry.

[44]  J. Wan,et al.  [Effect of indirubin on hemopoietic cell production (author's transl)]. , 1981, Zhongguo yao li xue bao = Acta pharmacologica Sinica.

[45]  L. Hartwell,et al.  Cell cycle control and cancer. , 1994, Science.

[46]  J. Harper,et al.  Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. , 1997, Molecular biology of the cell.

[47]  F. Tamanoi,et al.  Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines , 2000, Oncogene.

[48]  Ji Xj,et al.  [Studies on the antineoplastic action and toxicity of synthetic indirubin (author's transl)]. , 1981 .

[49]  D. H. Walker.  Small-molecule inhibitors of cyclin-dependent kinases: molecular tools and potential therapeutics. , 1998, Current topics in microbiology and immunology.

[50]  P. Cohen,et al.  The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[51]  Rui Han,et al.  Highlight on the studies of anticancer drugs derived from plants in china , 1994, Stem cells.

[52]  L. Meijer,et al.  Chemical inhibitors of cyclin-dependent kinases , 1997 .

[53]  P. Greengard,et al.  Indirubins Inhibit Glycogen Synthase Kinase-3β and CDK5/P25, Two Protein Kinases Involved in Abnormal Tau Phosphorylation in Alzheimer's Disease , 2001, The Journal of Biological Chemistry.

[54]  L. Meijer,et al.  Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells , 2001, British Journal of Cancer.

[55]  G. Hannon,et al.  The INK4 family of CDK inhibitors. , 1998, Current topics in microbiology and immunology.