Abstract
The bis-indole indirubin is the active ingredient of the Traditional Chinese Medicine recipe Danggui Longhui Wan used against chronic myelocytic leukemia. We have previously shown that indirubins are potent inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3. We here investigated the anti-mitotic properties of this class of compounds using the cell permeable indirubin-3′-monoxime and the HBL-100 cell line. Indirubin-3′-monoxime reversibly arrests asynchronous HBL-100 cells in G2. This arrest is not accompanied by any significant change in expression of the major cell cycle regulators. However indirubin-3′-monoxime inhibits the phosphorylation of consensus CDK phosphorylation sites as well as of nucleolin at a specific CDK1/cyclin B phosphorylation site, suggesting a direct action on the mitotic CDK1/cyclin B. When indirubin-3′-monoxime is added to HBL-100 cells synchronized in M phase by nocodazole, cells undergo an endoreplication leading to an 8n DNA content. As soon as indirubin-3′-monoxime is washed away, these polyploid cells become aneuploid and later die from necrosis. This mechanism of endoreplication followed by cell death may contribute to the anti-tumour properties of indirubins.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- CDK:
-
cyclin-dependent kinase
- GAPDH:
-
glyceraldehyde 3-phosphate dehydrogenase
- PBS:
-
phosphate-buffered saline
- TBS:
-
Tris-buffered saline
References
Akiyama T, Shimizu M, Okabe M, Tamaoki T, Akinaga S . 1999 Anti-Cancer Drugs 10: 67–78
Atienza C, Elliott MJ, Dong YB, Yang HL, Stilwell A, Liu TJ, McMasters KM . 2000 Int. J. Mol. Med. 6: 55–63
Bates S, Ryan KM, Philips AC, Vousden KH . 1998 Oncogene 12: 1691–1703
Bible KC, Kaufmann SH . 1997 Cancer Res. 57: 3375–3380
Borgne A, Meijer . 1996 J. Biol. Chem. 271: 27847–27854
Borgne A, Meijer L . 1999 Médecine/Sciences 15: 496–503
Brodsky WY, Uryvaeva IV . 1977 Int. Rev. Cytol. 50: 275–332
Chang CN . 1985 Advances in Chinese Medicinal Materials Research. Chang HM, Yeung HW, Tso W, Koo A, (eds) World Scientific Publishing Company: Singapore pp. 369–376
Chen DH, Xie JX . 1984 Chinese Trad. Herbal Drugs 15: 6–8
Edamatsu H, Gau CL, Nemoto T, Guo L, Tamanoi F . 2000 Oncogene 19: 3059–3068
Hall LL, Th'ng JPH, Guo XW, Teplitz RL, Bradbury EM . 1996 Cancer Res. 56: 3551–3559
Han R . 1994 Stem Cells 12: 53–63
Hoebeke J, Van Nijen G, De Brabander M . 1976 Biochem. Biophys. Res. Commun. 69: 319–324
Hoessel R, Leclerc S, Endicott J, Noble M, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L . 1999 Nature Cell Biol. 1: 60–67
Ikegami Y, Yano S, Nakao K . 1996 Drug Res. 46: 201–204
Institute of Haematology, Chinese Academy of Medical Sciences . 1979 Chinese J. Intern. Med. 18: 83–88
Itzhaki JE, Gilbert CS, Porter ACG . 1997 Nature Genet. 15: 258–265
Ji XJ, Zhang FR . 1985 Acta Pharm. Sin. 20: 137–139
Ji XJ, Zhang FR, Lei JL, Xu YT . 1981 Acta Pharma. Sin. 16: 146–148
Klein PS, Melton DA . 1996 Proc. Natl. Acad. Sci. USA 93: 8455–8459
Lallemand F. Courilleau D, Buquet-Fagot C, Atfi A, Montagne MN, Mester J . 1999 Exp. Cell Res. 247: 432–440
Leclerc S, Garnier M, Hoessel R, Marko Bibb JA, Snyder GL, Greengard P, Biernat J, Mandelkow EM, Eisenbrand G, Meijer L . 2001 J. Biol. Chem. 276: 251–260
Li C, Go Y, Mao Z, Koyano K, Kai Y, Kaneshisa N, Zhu Q, Zhou Z, Wu S . 1996 Bull. Chem. Soc. Jpn. 69: 1621–1627
Ma M, Yao B . 1983 J. Trad. Chinese Med. 3: 245–248
Marko D, Schätzle S, Friedel A, Genzlinger A, Zankl H, Meijer L, Eisenbrand G . 2001 Br. J. Cancer 84: 283–289
Meijer L . 2000 Drug Resistance Update 3: 83–88
Meijer L, Kim SH . 1997 Methods Enzymol., ‘Cell Cycle Control’ 283: 113–128
Meijer L, Pondaven P . 1988 Exp. Cell Res. 174: 116–129
Niculescu AB, Chen X, Smeets M, Hengst L, Prives C, Reed SI . 1998 Mol. Cell. Biol. 18: 629–643
Ongkeko W, Ferguson DJP, Harris AL, Norbury C . 1995 J. Cell Sci. 108: 2897–2904
Roberge M, Berlinck RG, . Xu L, Anderson HJ, Lim LY, Curman D, Stringer CM, Friend SH, Davies P, Vincent I, Haggarty SJ, Kelly MT, Britton R, Piers E, Andersen RJ . 1998 Cancer Res. 58: 5701–5716
Romanowski P, Madine MA . 1996 Trends Cell Biol. 6: 184–188
Sichuan Institute of Traditional Chinese Medicine . 1981 Chinese Trad. Herb Drugs 12: 27–29
Stambolic V, Ruel L, Woodgett R . 1996 Curr. Biol. 6: 1664–1668
Tang W, Eisenbrand G . 1992 Chinese drugs of plant origin: chemistry, pharmacology, and use in traditional and modern medicine Springer-Verlag, Heidelberg
Usui T, Yoshida M, Abe K, Osada H, Isono K, Beppu T . 1991 J. Cell Biol. 115: 1275–1282
Vincent IJ, Rosado M, Davies P . 1996 J. Cell Biol. 132: 413–425
Wang JH, You YC, Mi, JX, Ying HG . 1981 Acta Pharm. Sinica, 2: 241–244
Wu KM, Zhang MY, Fang Z, Huang L . 1985 Acta Pharm. Sinica 20: 821–826
Wu LM, Yang YP, Zhu ZH . 1979 Comm. Chinese Herbal Med. 9: 6–8
Yamada K, Kimura G . 1985 J. Cell Physiol. 122: 59–68
Zhang ZN, Liu EK, Zheng TL . 1985 J. Trad. Chinese Medicine 5: 246–248
Zhu YP, Woerdenbag HJ . 1995 Pharm. World Sci. 17: 103–112
Acknowledgements
We are grateful to Dr P Davies. This research was supported by grants from the ‘Association pour la Recherche sur le Cancer’ (ARC 5343) (L Meijer) and the ‘Conseil Régional de Bretagne’ (L Meijer).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Damiens, E., Baratte, B., Marie, D. et al. Anti-mitotic properties of indirubin-3′-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest. Oncogene 20, 3786–3797 (2001). https://doi.org/10.1038/sj.onc.1204503
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204503
Keywords
This article is cited by
-
Synergistic effect of plasma-activated medium and novel indirubin derivatives on human skin cancer cells by activation of the AhR pathway
Scientific Reports (2022)
-
Targeting the Wnt signaling pathway for breast cancer bone metastasis therapy
Journal of Molecular Medicine (2022)
-
Indirubin inhibits the migration, invasion, and activation of fibroblast-like synoviocytes from rheumatoid arthritis patients
Inflammation Research (2017)
-
Induction of atypical cell death in thyroid carcinoma cells by the indirubin derivative 7-bromoindirubin-3′-oxime (7BIO)
Cancer Cell International (2015)
-
Indirubin derivative E804 inhibits angiogenesis
BMC Cancer (2012)