Skip to main content
SpringerLink
Log in

The “survivin suppressants” NSC 80467 and YM155 induce a DNA damage response

  • Short Communication
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 30 September 2012

Abstract

Purpose

To establish whether NSC80467, a novel fused naphthquinone imidazolium, has a similar spectrum of activity to the well-characterized “survivin suppressant” YM155 and to extend mechanistic studies for this structural class of agent.

Methods

NSC80467 and YM155 were analyzed in parallel using assays measuring viability, survivin suppression, inhibition of DNA/RNA/protein synthesis and the cellular response to DNA damage.

Results

GI50 values generated for both compounds in the NCI-60 screen yielded a correlation coefficient of 0.748, suggesting significant concordance. Both agents were also shown to inhibit protein expression of survivin [BIRC5]. COMPARE analysis identified DNA damaging agents chromomycin A3 and bisantrene HCl and one DNA-directed inhibitor of transcription, actinomycin D, as correlating with the activity of NSC80467 and YM155. Furthermore, both agents were shown to preferentially inhibit DNA, over RNA and protein synthesis. Thus, the ability of NSC80467 and YM155 to induce a DNA damage response was examined further. Treatment of PC3 cells with either agent resulted in dose-dependent induction of γH2AX and pKAP1, two markers of DNA damage. The concentrations of agent required to stimulate γH2AX were considerably lower than those required to inhibit survivin, implicating DNA damage as an initiating event. The DNA damage response was then confirmed in a panel of cell lines treated with NSC80467 or YM155, suggesting that γH2AX and pKAP1 have potential as response biomarkers.

Conclusions

These data provide the first evidence that NSC80467 and YM155 are DNA damaging agents where suppression of survivin is a secondary event, likely a consequence of transcriptional repression.

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

References

  1. Bates SE, Wilson WH, Fojo AT, Alvarez M, Zhan Z, Regis J, Robey R, Hose C, Monks A, Kang YK, Chabner B (1996) Clinical reversal of multidrug resistance. Oncologist 1(4):269–275

    PubMed  Google Scholar 

  2. Alvarez M, Paull K, Monks A, Hose C, Lee JS, Weinstein J, Grever M, Bates S, Fojo T (1995) Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J Clin Invest 95(5):2205–2214. doi:10.1172/JCI117910

    Article  PubMed  CAS  Google Scholar 

  3. Nakahara T, Takeuchi M, Kinoyama I, Minematsu T, Shirasuna K, Matsuhisa A, Kita A, Tominaga F, Yamanaka K, Kudoh M, Sasamata M (2007) YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67(17):8014–8021. doi:10.1158/0008-5472.CAN-07-1343

    Article  PubMed  CAS  Google Scholar 

  4. Cheson BD, Bartlett NL, Vose JM, Lopez-Hernandez A, Seiz AL, Keating AT, Shamsili S (2011) A phase II study of the survivin suppressant YM155 in patients with refractory diffuse large B-cell lymphoma. Cancer. doi:10.1002/cncr.26510

    PubMed  Google Scholar 

  5. Tolcher AW, Quinn DI, Ferrari A, Ahmann F, Giaccone G, Drake T, Keating A, de Bono JS (2011) A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer. Ann Oncol. doi:10.1093/annonc/mdr353

    PubMed  Google Scholar 

  6. Lewis KD, Samlowski W, Ward J, Catlett J, Cranmer L, Kirkwood J, Lawson D, Whitman E, Gonzalez R (2011) A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. Invest New Drugs 29(1):161–166. doi:10.1007/s10637-009-9333-6

    Article  PubMed  CAS  Google Scholar 

  7. Giaccone G, Zatloukal P, Roubec J, Floor K, Musil J, Kuta M, van Klaveren RJ, Chaudhary S, Gunther A, Shamsili S (2009) Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. J Clin Oncol 27(27):4481–4486. doi:10.1200/JCO.2008.21.1862

    Article  PubMed  CAS  Google Scholar 

  8. Tang H, Shao H, Yu C, Hou J (2011) Mcl-1 downregulation by YM155 contributes to its synergistic anti-tumor activities with ABT-263. Biochem Pharmacol 82(9):1066–1072. doi:10.1016/j.bcp.2011.07.064

    Article  PubMed  CAS  Google Scholar 

  9. Paull KD, Shoemaker RH, Hodes L, Monks A, Scudiero DA, Rubinstein L, Plowman J, Boyd MR (1989) Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. J Natl Cancer Inst 81(14):1088–1092

    Article  PubMed  CAS  Google Scholar 

  10. Stockwin LH, Yu SX, Stotler H, Hollingshead MG, Newton DL (2009) ARC (NSC 188491) has identical activity to Sangivamycin (NSC 65346) including inhibition of both P-TEFb and PKC. BMC Cancer 9:63. doi:10.1186/1471-2407-9-63

    Article  PubMed  Google Scholar 

  11. Chatterjee S, Zaman K, Ryu H, Conforto A, Ratan RR (2001) Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons. Ann Neurol 49(3):345–354

    Article  PubMed  CAS  Google Scholar 

  12. Foye WO, Karnik PS, Sengupta SK (1986) DNA-binding abilities of bisguanylhydrazones of anthracene-9,10-dicarboxaldehyde. Anticancer Drug Des 1(2):65–71

    PubMed  CAS  Google Scholar 

  13. Sobell HM (1985) Actinomycin and DNA transcription. Proc Natl Acad Sci USA 82(16):5328–5331

    Article  PubMed  CAS  Google Scholar 

  14. Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S, Pommier Y (2008) GammaH2AX and cancer. Nat Rev Cancer 8(12):957–967. doi:10.1038/nrc2523

    Article  PubMed  CAS  Google Scholar 

  15. Li X, Lee YK, Jeng JC, Yen Y, Schultz DC, Shih HM, Ann DK (2007) Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. J Biol Chem 282(50):36177–36189. doi:10.1074/jbc.M706912200

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Biological Testing Branch, Developmental Therapeutics Program, Building 320, Room 9, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, 21702, USA

    Trevor G. Glaros, Luke H. Stockwin, Michael E. Mullendore, Brian Smith, Bethanie L. Morrison & Dianne L. Newton

Authors
  1. Trevor G. Glaros
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luke H. Stockwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael E. Mullendore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bethanie L. Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dianne L. Newton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dianne L. Newton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Glaros, T.G., Stockwin, L.H., Mullendore, M.E. et al. The “survivin suppressants” NSC 80467 and YM155 induce a DNA damage response. Cancer Chemother Pharmacol 70, 207–212 (2012). https://doi.org/10.1007/s00280-012-1868-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-012-1868-0

Keywords

Search

Navigation