Skip to main content

Advertisement

SpringerLink
Log in

MT7, a novel compound from a combinatorial library, arrests mitosis via inhibiting the polymerization of microtubules

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Targeting cellular mitosis is an attractive antitumor strategy. Here, we reported MT7, a novel compound from the 6H-Pyrido[2′,1′:2,3]imidazo [4,5-c]isoquinolin- 5(6H)-one library generated by using the multi-component reaction strategy, as a new mitotic inhibitor. MT7 elicited apparent inhibition of cell proliferation by arresting mitosis specifically and reversibly in various tumor cell lines originating from different human tissues. Detailed mechanistic studies revealed that MT7 induced typical gene expression profiles related to mitotic arrest shown by cDNA microarray assays. Connectivity Map was used to analyze the microarray data and suggested that MT7 was possibly a tubulin inhibitor due to its similar gene expression profiles to those of the known tubulin inhibitors demecolcine, celastrol and paclitaxel. Further analyses demonstrated that MT7 inhibited the polymerization of cellular microtubules although it was not detectable to bind to purified tubulin. The inhibition of cellular tubulin polymerization by MT7 subsequently resulted in the disruption of mitotic spindle formation, activated the spindle assembly checkpoint and consequently arrested the cells at mitosis. The persistent mitotic arrest by the treatment with MT7 led the tested tumor cells to apoptosis. Our data indicate that MT7 could act as a promising lead for further optimization, in hopes of developing new anticancer therapeutics and being used to probe the biology of mitosis, specifically, the mode of interference with microtubules.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

MT7:

6-(4-methoxybenzyl)pyrido[2′,1′:2,3] imidazo[4,5-c]isoquinolin-5(6H)-one

VCR:

vincristine

DMSO:

dimethyl sulfoxide

SRB:

sulforhodamine B

siRNA:

small interfering RNA

GSEA:

gene set enrichment analysis

SAC:

spindle assembly checkpoint

IC50 :

50% inhibitory concentration

Topo I:

topoisomerase I

Topo II:

topoisomerase II.

References

  1. Sherr CJ (1996) Cancer Cell Cycles. Science 274:1672–1677

    Article  CAS  PubMed  Google Scholar 

  2. Castedo M, Perfettini J-L, Roumier T et al (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23:2825–2837

    Article  CAS  PubMed  Google Scholar 

  3. Wood KW (2001) Past and future of the mitotic spindle as an oncology target. Curr. Opin. Pharmacol. 1:370–377

    Article  CAS  PubMed  Google Scholar 

  4. Jackson JR, Patrick DR, Dar MM et al (2007) Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer 7:107–117

    Article  CAS  PubMed  Google Scholar 

  5. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265

    Article  CAS  PubMed  Google Scholar 

  6. Pinguet F, Mavel S, Galtier C et al (1999) Synthesis and cytotoxicity of novel pyrido[1, 2-e]purines on multidrug resistant human MCF7 cells. Pharmazie 54:876–878

    CAS  PubMed  Google Scholar 

  7. Adhikary PF, Das SK, Hess BA Jr (1976) Synthesis and antihypertensive activity of some imidazoindole derivatives. J Med Chem 19:1352–1354

    Article  CAS  PubMed  Google Scholar 

  8. Meng T, Zhang Z, Hu D et al (2007) Three-component combinatorial synthesis of a substituted 6H-pyrido[2′, 1′:2, 3]imidazo- [4, 5-c]isoquinolin-5(6H)-one library with cytotoxic activity. J Comb Chem 9:739–741

    Article  CAS  PubMed  Google Scholar 

  9. Ditchfield C, Johnson VL, Tighe A et al (2003) Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J. Cell Biol. 161:267–280

    Article  CAS  PubMed  Google Scholar 

  10. Andreassen PR, Skoufias DA, Margolis RL (2004) Analysis of the spindle-assembly checkpoint in HeLa cells. Methods Mol Biol 281:213–225

    CAS  PubMed  Google Scholar 

  11. Shelanski ML, Gaskin F, Cantor CR (1973) Microtubule assembly in the absence of added nucleotides. Proc Natl Acad Sci U S A 70:765–768

    Article  CAS  PubMed  Google Scholar 

  12. Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550

    Article  CAS  PubMed  Google Scholar 

  13. Mootha VK, Lindgren CM, Eriksson K-F et al (2003) PGC-1[alpha]-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273

    Article  CAS  PubMed  Google Scholar 

  14. Lamb J, Crawford ED, Peck D et al (2006) The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease. Science 313:1929–1935

    Article  CAS  PubMed  Google Scholar 

  15. Lamb J (2007) The Connectivity Map: a new tool for biomedical research. Nat Rev Cancer 7:54–60

    Article  CAS  PubMed  Google Scholar 

  16. Yamashita Y, Fujii N, Murakata C et al (1992) Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry 31:12069–12075

    Article  CAS  PubMed  Google Scholar 

  17. Meng LH, Zhang JS, Ding J (2001) Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects by trapping enzyme-DNA cleavage complexes. Biochem Pharmacol 62:733–741

    Article  CAS  PubMed  Google Scholar 

  18. Qin Y, Meng L, Hu C et al (2007) Gambogic acid inhibits the catalytic activity of human topoisomerase IIalpha by binding to its ATPase domain. Mol Cancer Ther 6:2429–2440

    Article  CAS  PubMed  Google Scholar 

  19. Tanabe K, Ikegami Y, Ishida R et al (1991) Inhibition of topoisomerase II by antitumor agents bis(2, 6-dioxopiperazine) derivatives. Cancer Res 51:4903–4908

    CAS  PubMed  Google Scholar 

  20. Bruce Alberts AJ, Lewis J, Raff M, Roberts K, Walter P (2002) Molecular Biology of the Cell. Garland Science, New York

    Google Scholar 

  21. Pagano M, Pepperkok R, Verde F et al (1992) Cyclin A is required at two points in the human cell cycle. EMBO J 11:961–971

    CAS  PubMed  Google Scholar 

  22. Clute P, Pines J (1999) Temporal and spatial control of cyclin B1 destruction in metaphase. Nat Cell Biol 1:82–87

    Article  CAS  PubMed  Google Scholar 

  23. di Bernardo D, Thompson MJ, Gardner TS et al (2005) Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks. Nat Biotechnol 23:377–383

    Article  PubMed  Google Scholar 

  24. Cho RJ, Campbell MJ, Winzeler EA et al (1998) A genome-wide transcriptional analysis of the mitotic cell cycle. Mol Cell 2:65–73

    Article  CAS  PubMed  Google Scholar 

  25. Whitfield ML, Sherlock G, Saldanha AJ et al (2002) Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 13:1977–2000

    Article  CAS  PubMed  Google Scholar 

  26. Jiang Y, Liu M, Spencer CA et al (2004) Involvement of transcription termination factor 2 in mitotic repression of transcription elongation. Mol Cell 14:375–385

    Article  CAS  PubMed  Google Scholar 

  27. Parsons GG, Spencer CA (1997) Mitotic repression of RNA polymerase II transcription is accompanied by release of transcription elongation complexes. Mol Cell Biol 17:5791–5802

    CAS  PubMed  Google Scholar 

  28. Gottesfeld JM, Forbes DJ (1997) Mitotic repression of the transcriptional machinery. Trends Biochem Sci 22:197–202

    Article  CAS  PubMed  Google Scholar 

  29. Hartl P, Gottesfeld J, Forbes DJ (1993) Mitotic repression of transcription in vitro. J Cell Biol 120:613–624

    Article  CAS  PubMed  Google Scholar 

  30. Spencer CA, Kruhlak MJ, Jenkins HL et al (2000) Mitotic transcription repression in vivo in the absence of nucleosomal chromatin condensation. J Cell Biol 150:13–26

    Article  CAS  PubMed  Google Scholar 

  31. Vivanco I, Palaskas N, Tran C et al (2007) Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell 11:555–569

    Article  CAS  PubMed  Google Scholar 

  32. Baur JA, Pearson KJ, Price NL et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    Article  CAS  PubMed  Google Scholar 

  33. Cabral F, Sobel ME, Gottesman MM (1980) CHO mutants resistant to colchicine, colcemid or griseofulvin have an altered beta-tubulin. Cell 20:29–36

    Article  CAS  PubMed  Google Scholar 

  34. Banerjee AC, Bhattacharyya B (1979) Colcemid and colchicine binding to tubulin. Similarity and dissimilarity. FEBS Lett 99:333–336

    Article  CAS  PubMed  Google Scholar 

  35. Morita H, Hirasawa Y, Muto A et al (2008) Antimitotic quinoid triterpenes from Maytenus chuchuhuasca. Bioorg Med Chem Lett 18:1050–1052

    Article  CAS  PubMed  Google Scholar 

  36. Peters NT, Logan KO, Miller AC et al (2007) Phospholipase D signaling regulates microtubule organization in the fucoid alga Silvetia compressa. Plant Cell Physiol 48:1764–1774

    Article  CAS  PubMed  Google Scholar 

  37. Dhonukshe P, Laxalt AM, Goedhart J et al (2003) Phospholipase D Activation Correlates with Microtubule Reorganization in Living Plant Cells. Plant Cell 15:2666–2679

    Article  CAS  PubMed  Google Scholar 

  38. Kadura S, Sazer S (2005) SAC-ing mitotic errors: how the spindle assembly checkpoint (SAC) plays defense against chromosome mis-segregation. Cell Motil Cytoskeleton 61:145–160

    Article  CAS  PubMed  Google Scholar 

  39. Yamada HY, Gorbsky GJ (2006) Spindle checkpoint function and cellular sensitivity to antimitotic drugs. Mol Cancer Ther 5:2963–2969

    Article  CAS  PubMed  Google Scholar 

  40. Rieder CL, Maiato H (2004) Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 7:637–651

    Article  CAS  PubMed  Google Scholar 

  41. Steegmaier M (2005) BI 2536, a potent and highly selective inhibitor of Polo-like kinase 1 (Plk1), induces mitotic arrest and apoptosis in a broad spectrum of tumor cell lines. Clin. Cancer Res. 11:9147

    Google Scholar 

  42. Mayer TU (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–974

    Article  CAS  PubMed  Google Scholar 

  43. Tao W (2005) Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 8:49–59

    Article  CAS  PubMed  Google Scholar 

  44. Keen N, Taylor S (2004) Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer 4:927–936

    Article  CAS  Google Scholar 

  45. Soncini C, Carpinelli P, Gianellini L et al (2006) PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity. Clin Cancer Res 12:4080–4089

    Article  CAS  PubMed  Google Scholar 

  46. Donaldson MM, Tavares AA, Hagan IM et al (2001) The mitotic roles of Polo-like kinase. J Cell Sci 114:2357–2358

    CAS  PubMed  Google Scholar 

  47. Marumoto T, Zhang D, Saya H (2005) Aurora-A — a guardian of poles. Nat Rev Cancer 5:42–50

    Article  CAS  PubMed  Google Scholar 

  48. Huang M, Gao H, Chen Y et al (2007) Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo. Clin Cancer Res 13:1298–1307

    Article  CAS  PubMed  Google Scholar 

  49. Bhat KM, Setaluri V (2007) Microtubule-associated proteins as targets in cancer chemotherapy. Clin Cancer Res 13:2849–2854

    Article  CAS  PubMed  Google Scholar 

  50. Charbaut E, Curmi PA, Ozon S et al (2001) Stathmin Family Proteins Display Specific Molecular and Tubulin Binding Properties. J. Biol. Chem. 276:16146–16154

    Article  CAS  PubMed  Google Scholar 

  51. Wignall SM, Gray NS, Chang YT et al (2004) Identification of a novel protein regulating microtubule stability through a chemical approach. Chem Biol 11:135–146

    CAS  PubMed  Google Scholar 

  52. Fourest-Lieuvin A, Peris L, Gache V et al (2006) Microtubule Regulation in Mitosis: Tubulin Phosphorylation by the Cyclin-dependent Kinase Cdk1. Mol Biol Cell 17:1041–1050

    Article  CAS  PubMed  Google Scholar 

  53. Matsuyama A, Shimazu T, Sumida Y et al (2002) In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J 21:6820–6831

    Article  CAS  PubMed  Google Scholar 

  54. Zhang Y, Li N, Caron C et al (2003) HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J 22:1168–1179

    Article  CAS  PubMed  Google Scholar 

  55. Schiff PB, Horwitz SB (1981) Taxol assembles tubulin in the absence of exogenous guanosine 5′-triphosphate or microtubule-associated proteins. Biochemistry 20:3247–3252

    Article  CAS  PubMed  Google Scholar 

  56. Edsall AB, Mohanakrishnan AK, Yang D et al (2004) Effects of Altering the Electronics of 2-Methoxyestradiol on Cell Proliferation, on Cytotoxicity in Human Cancer Cell Cultures, and on Tubulin Polymerization. J Med Chem 47:5126–5139

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the grants from the National Natural Science Foundation of China (NSFC) (No.30873092 and No.30721005) and the Science and Technology Commission of Shanghai Municipality (STCSM) (No.08PJ14113 and No.08DZ1980200), respectively.

We sincerely thank Dr. Yi Chen, Mrs. Li-Juan Lu, Mr. Yong Xi and Dr. Hong-Chun Liu for their technical supports.

The authors have no conflicting financial interests.

Author information

Authors and Affiliations

  1. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China

    Zhixiang Zhang, Jingxue He, Ming Li, Lin-Jiang Tong, Liping Lin, Ze-Hong Miao & Jian Ding

  2. Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China

    Tao Meng, Bing Xiong & Jingkang Shen

Authors
  1. Zhixiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tao Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jingxue He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lin-Jiang Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bing Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liping Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jingkang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ze-Hong Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jian Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ze-Hong Miao or Jian Ding.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Z., Meng, T., He, J. et al. MT7, a novel compound from a combinatorial library, arrests mitosis via inhibiting the polymerization of microtubules. Invest New Drugs 28, 715–728 (2010). https://doi.org/10.1007/s10637-009-9303-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-009-9303-z

Keywords

Search

Navigation