Skip to main content
SpringerLink
Log in

Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor

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

Summary

Hemiasterlins are cytotoxic tripeptides with antimicrotubule activity originally isolated from marine sponges. We have developed new hemiasterlin derivatives BF65 and BF78 that are highly potent to induce cancer cell death in the low nanomolar range. Examination of their mechanisms of cell cycle arrest and disruption of microtubules revealed an unusual characteristic in addition to anti-tubulin effect. Immunofluorescence staining revealed that A549 lung carcinoma cells treated with BF65 or BF78 exhibited both monopolar and multipolar mitotic spindles. Centrosomes were separated with short spindle microtubules in cells with multipolar spindles. In vitro tubulin polymerization assay confirmed that both BF65 and BF78 were highly potent to inhibit tubulin polymerization. These two compounds induced the formation of monoastral spindles suggesting that they might be inhibitors of mitotic kinesins such as KSP/Eg5. However, kinetic measurement of microtubule activated kinesin ATPase activity demonstrated that unlike the positive control monastrol, neither BF65 nor BF78 suppressed KSP/Eg5 activity. Hence the effect may be a variant form of tubulin inhibition. Similar to vinca alkaloids, BF compounds synergized with a colchicine site microtubule inhibitor stilbene 5c both in vitro and in vivo, which may provide a potential drug combination in the future clinical application.

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

References

  1. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265. doi:10.1038/nrc1317

    Article  CAS  PubMed  Google Scholar 

  2. Rowinsky EK, Calvo E (2006) Novel agents that target tublin and related elements. Semin Oncol 33:421–435. doi:10.1053/j.seminoncol.2006.04.006

    Article  CAS  PubMed  Google Scholar 

  3. Stevenson JP, Rosen M, Sun W et al (2003) Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J Clin Oncol 21:4428–4438. doi:10.1200/JCO.2003.12.986

    Article  CAS  PubMed  Google Scholar 

  4. Cooney MM, Radivoyevitch T, Dowlati A et al (2004) Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer. Clin Cancer Res 10:96–100. doi:10.1158/1078-0432.CCR-0364-3

    Article  CAS  PubMed  Google Scholar 

  5. Rustin GJ, Galbraith SM, Anderson H et al (2003) Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J Clin Oncol 21:2815–2822. doi:10.1200/JCO.2003.05.185

    Article  CAS  PubMed  Google Scholar 

  6. Anderson HL, Yap JT, Miller MP, Robbins A, Jones T, Price PM (2003) Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate. J Clin Oncol 21:2823–2830. doi:10.1200/JCO.2003.05.186

    Article  CAS  PubMed  Google Scholar 

  7. Blakey DC, Westwood FR, Walker M et al (2002) Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models. Clin Cancer Res 8:1974–1983

    CAS  PubMed  Google Scholar 

  8. Beerepoot LV, Radema SA, Witteveen EO et al (2006) Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491–1498. doi:10.1200/JCO.2005.02.7458

    Article  CAS  PubMed  Google Scholar 

  9. Nabha SM, Mohammad RM, Dandashi MH et al (2002) Combretastatin-A4 prodrug induces mitotic catastrophe in chronic lymphocytic leukemia cell line independent of caspase activation and poly (ADP-ribose) polymerase cleavage. Clin Cancer Res 8:2735–2741

    CAS  PubMed  Google Scholar 

  10. Jackson JR, Patrick DR, Dar MM, Huang PS (2007) Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer 7:107–117. doi:10.1038/nrc2049

    Article  CAS  PubMed  Google Scholar 

  11. Malumbres M (2006) Therapeutic opportunities to control tumor cell cycles. Clin Transl Oncol 8:399–408. doi:10.1007/s12094-006-0193-7

    Article  CAS  PubMed  Google Scholar 

  12. Swanton C (2004) Cell-cycle targeted therapies. Lancet Oncol 5:27–36. doi:10.1016/S1470-2045(03)01321-4

    Article  CAS  PubMed  Google Scholar 

  13. Dai Y, Grant S (2004) Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents. Curr Oncol Rep 6:123–130. doi:10.1007/s11912-004-0024-3

    Article  PubMed  Google Scholar 

  14. Manfredi MG, Ecsedy JA, Meetze KA et al (2007) Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A 104:4106–4111. doi:10.1073/pnas.0608798104

    Article  CAS  PubMed  Google Scholar 

  15. Tyler RK, Shpiro N, Marquez R, Eyers PA (2007) VX-680 inhibits Aurora A and Aurora B kinase activity in human cells. Cell Cycle 6:2846–2854. doi:10.4161/cc.6.22.4940

    Article  CAS  PubMed  Google Scholar 

  16. McInnes C, Mezna M, Fischer PM (2005) Progress in the discovery of polo-like kinase inhibitors. Curr Top Med Chem 5:181–197

    Article  CAS  PubMed  Google Scholar 

  17. Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286:971–974. doi:10.1126/science.286.5441.971

    Article  CAS  PubMed  Google Scholar 

  18. Tang PA, Siu LL, Chen EX et al (2008) Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 26:257–264. doi:10.1007/s10637-007-9098-8

    Article  CAS  PubMed  Google Scholar 

  19. Lee CW, Bélanger K, Rao SC et al (2008) A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs 26:249–255. doi:10.1007/s10637-007-9097-9

    Article  CAS  PubMed  Google Scholar 

  20. Valentine MT, Fordyce PM, Block SM (2006) Eg5 steps it up! Cell Div 1:31. doi:10.1186/1747-1028-1-31

    Article  PubMed  Google Scholar 

  21. Bergnes G, Brejc K, Belmont L (2005) Mitotic kinesins: prospects for antimitotic drug discovery. Curr Top Med Chem 5:127–145. doi:10.2174/1568026053507697

    Article  CAS  PubMed  Google Scholar 

  22. Cao TM, Durrant D, Tripathi A et al (2008) Stilbene derivatives that are colchicine site microtubule inhibitors have anti-leukemic activity and minimal systemic toxicity. Am J Hematol 83:390–397. doi:10.1002/ajh.21104

    Article  CAS  PubMed  Google Scholar 

  23. Bai R, Durso NA, Sackett DL, Hamel E (1999) Interactions of the sponge-derived antimitotic tripeptide hemiasterlin with tubulin: comparison with dolastatin 10 and cryptophycin 1. Biochemistry 38:14302–14310. doi:10.1021/bi991323e

    Article  CAS  PubMed  Google Scholar 

  24. Loganzo F, Discafani CM, Annable T et al (2003) HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivo. Cancer Res 63:1838–1845

    CAS  PubMed  Google Scholar 

  25. Nieman JA, Coleman JE, Wallace DJ et al (2003) Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues. J Nat Prod 66:183–199. doi:10.1021/np020375t

    Article  CAS  PubMed  Google Scholar 

  26. Perez EA, Hillman DW, Fishkin PA et al (2005) Phase II trial of dolastatin-10 in patients with advanced breast cancer. Invest New Drugs 23:257–261. doi:10.1007/s10637-005-6735-y

    Article  CAS  PubMed  Google Scholar 

  27. Kindler HL, Tothy PK, Wolff R et al (2005) Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers. Invest New Drugs 23:489–493. doi:10.1007/s10637-005-2909-x

    Article  CAS  PubMed  Google Scholar 

  28. Kuznetsov G, TenDyke K, Towle MJ et al (2009) Tubulin-based antimitotic mechanism of E7974, a novel analogue of the marine sponge natural product hemiasterlin. Mol Cancer Ther 8:2852–2860. doi:10.1158/1535-7163.MCT-09-0301

    Article  CAS  PubMed  Google Scholar 

  29. Durrant D, Richard J, Tripathi A et al (2009) Development of water soluble derivatives of cis-3, 4′, 5-trimethoxy-3′-aminostilbene for optimization and use in cancer therapy. Invest New Drugs 27:41–52. doi:10.1007/s10637-008-9139-y

    Article  CAS  PubMed  Google Scholar 

  30. Webb MR (1992) A continuous spectrophotometric assay for inorganic phosphate and for measuring phosphate release kinetics in biological systems. Proc Natl Acad Sci U S A 89:4884–4887

    Article  CAS  PubMed  Google Scholar 

  31. Wang LG, Liu XM, Kreis W, Budman DR (1999) The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol 44:355–361

    Article  CAS  PubMed  Google Scholar 

  32. Millar JB, McGowan CH, Lenaers G, Jones R, Russell P (1991) p80cdc25 mitotic inducer is the tyrosine phosphatase that activates p34cdc2 kinase in fission yeast. EMBO J 10:4301–4309

    CAS  PubMed  Google Scholar 

  33. Lopez-Girona A, Furnari B, Mondesert O, Russell P (1999) Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein. Nature 397:172–175. doi:10.1038/16488

    Article  CAS  PubMed  Google Scholar 

  34. Gigant B, Wang C, Ravelli RB et al (2005) Structural basis for the regulation of tubulin by vinblastine. Nature 435:519–522. doi:10.1038/nature03566

    Article  CAS  PubMed  Google Scholar 

  35. Ravelli RB, Gigant B, Curmi PA et al (2004) Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 428:198–202. doi:10.1038/nature02393

    Article  CAS  PubMed  Google Scholar 

  36. Nunes M, Kaplan J, Wooters J et al (2005) Two photo affinity analogues of tripeptide, hemiasterlin, exclusively label alpha-tubulin. Biochemistry 44:6844–6857. doi:10.1021/bi0474766

    Article  CAS  PubMed  Google Scholar 

  37. Ravi M, Zask A, Rush TS 3rd (2005) Structure-based identification of the binding site for the hemiasterlin analogue HTI-286 on tubulin. Biochemistry 44:15871–15879. doi:10.1021/bi051268b

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Massey Cancer Center and Virginia Commonwealth University pilot program (R.M.L.), National Cancer Institute Grant R01CA111436 and fund from the National Taiwan University (L.C.H.).

Author information

Authors and Affiliations

  1. School of Pharmacy, National Taiwan University, 12F, No. 1, Section 1, Jen-Ai Road, Taipei, 10051, Taiwan

    Lih-Ching Hsu & Ching-Chun Huang

  2. Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA

    David E. Durrant

  3. Research Service, VA San Diego Healthcare System, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    Nai-Wen Chi

  4. Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy

    Riccardo Baruchello, Riccardo Rondanin, Cinzia Rullo, Paolo Marchetti, Giuseppina Grisolia & Daniele Simoni

  5. Lestoni Corp, Richmond, VA, USA

    Ray M. Lee

Authors
  1. Lih-Ching Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David E. Durrant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ching-Chun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nai-Wen Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Riccardo Baruchello
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Riccardo Rondanin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cinzia Rullo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paolo Marchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppina Grisolia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniele Simoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ray M. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lih-Ching Hsu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsu, LC., Durrant, D.E., Huang, CC. et al. Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor. Invest New Drugs 30, 1379–1388 (2012). https://doi.org/10.1007/s10637-011-9702-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-011-9702-9

Keywords

Search

Navigation