Skip to main content

Advertisement

SpringerLink
Log in

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines

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

Summary

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5′DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.

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

Similar content being viewed by others

References

  1. UCSW G (2009) United States Cancer Statistics: 1999–2005 incidence and mortality. Web Based Report, 2009

  2. Winter-Roach BA, Kitchener HC, Dickinson HO (2009) Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Syst Rev CD004706

  3. Vernooij F, Heintz AP, Witteveen PO, van der Heiden-van der Loo M, Coebergh JW, van der Graaf Y (2008) Specialized care and survival of ovarian cancer patients in The Netherlands: nationwide cohort study. J Natl Cancer Inst 100:399–406

    Article  PubMed  Google Scholar 

  4. Bast RC Jr, Hennessy B, Mills GB (2009) The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 9:415–428

    Article  PubMed  CAS  Google Scholar 

  5. Collinson F, Jayson G (2009) New therapeutic agents in ovarian cancer. Curr Opin Obstet Gynecol 21:44–53

    Article  PubMed  Google Scholar 

  6. Martin LP, Schilder RJ (2009) Management of recurrent ovarian carcinoma: current status and future directions. Semin Oncol 36:112–125

    Article  PubMed  Google Scholar 

  7. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784

    Article  PubMed  CAS  Google Scholar 

  8. Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K (2007) Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. Clin Cancer Res 13:4882–4890

    Article  PubMed  CAS  Google Scholar 

  9. Lee YS, Lim KH, Guo X, Kawaguchi Y, Gao Y, Barrientos T, Ordentlich P, Wang XF, Counter CM, Yao TP (2008) The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis. Cancer Res 68:7561–7569

    Article  PubMed  CAS  Google Scholar 

  10. Schrump DS (2009) Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin Cancer Res 15:3947–3957

    Article  PubMed  CAS  Google Scholar 

  11. Simms-Waldrip T, Rodriguez-Gonzalez A, Lin T, Ikeda AK, Fu C, Sakamoto KM (2008) The aggresome pathway as a target for therapy in hematologic malignancies. Mol Genet Metab 94:283–286

    Article  PubMed  CAS  Google Scholar 

  12. Prince HM, Bishton MJ, Harrison SJ (2009) Clinical studies of histone deacetylase inhibitors. Clin Cancer Res 15:3958–3969

    Article  PubMed  CAS  Google Scholar 

  13. Takai N, Kawamata N, Gui D, Said JW, Miyakawa I, Koeffler HP (2004) Human ovarian carcinoma cells: histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis. Cancer 101:2760–2770

    Article  PubMed  CAS  Google Scholar 

  14. Takai N, Narahara H (2007) Human endometrial and ovarian cancer cells: histone deacetylase inhibitors exhibit antiproliferative activity, potently induce cell cycle arrest, and stimulate apoptosis. Curr Med Chem 14:2548–2553

    Article  PubMed  CAS  Google Scholar 

  15. Modesitt SC, Sill M, Hoffman JS, Bender DP (2008) A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 109:182–186

    Article  PubMed  CAS  Google Scholar 

  16. Prince HM, Bishton MJ, Johnstone RW (2009) Panobinostat (LBH-589589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. Future Oncol 5:601–612

    Article  PubMed  CAS  Google Scholar 

  17. Yang YT, Balch C, Kulp SK, Mand MR, Nephew KP, Chen CS (2009) A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer. Neoplasia 11:552–563, 553 p following 563

    PubMed  CAS  Google Scholar 

  18. Budman DR, Calabro A (2004) Studies of synergistic and antagonistic combinations of conventional cytotoxic agents with the multiple eicosanoid pathway modulator LY 293111. Anticancer Drugs 15:877–881

    Article  PubMed  CAS  Google Scholar 

  19. Budman DR, Calabro A (2006) Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin: in vitro isobologram studies with conventional and nonconventional cytotoxic agents. Oncology 70:147–153

    Article  PubMed  CAS  Google Scholar 

  20. Budman DR, Soong R, Calabro A, Tai J, Diasio R (2006) Identification of potentially useful combinations of epidermal growth factor receptor tyrosine kinase antagonists with conventional cytotoxic agents using median effect analysis. Anticancer Drugs 17:921–928

    Article  PubMed  CAS  Google Scholar 

  21. Budman DR, Tai J, Calabro A (2007) Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro. Breast Cancer Res Treat 104:93–101

    Article  PubMed  CAS  Google Scholar 

  22. Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681

    Article  PubMed  CAS  Google Scholar 

  23. Chou TC (2008) Preclinical versus clinical drug combination studies. Leuk Lymphoma 49:2059–2080

    Article  PubMed  Google Scholar 

  24. Zhao L, Wientjes MG, Au JL (2004) Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res 10:7994–8004

    Article  PubMed  CAS  Google Scholar 

  25. Ikediobi ON, Davies H, Bignell G, Edkins S, Stevens C, O’Meara S, Santarius T, Avis T, Barthorpe S, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Hunter C, Jenkinson A, Jones D, Kosmidou V, Lugg R, Menzies A, Mironenko T, Parker A, Perry J, Raine K, Richardson D, Shepherd R, Small A, Smith R, Solomon H, Stephens P, Teague J, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Reinhold W, Weinstein JN, Stratton MR, Futreal PA, Wooster R (2006) Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. Mol Cancer Ther 5:2606–2612

    Article  PubMed  CAS  Google Scholar 

  26. Roschke AV, Tonon G, Gehlhaus KS, McTyre N, Bussey KJ, Lababidi S, Scudiero DA, Weinstein JN, Kirsch IR (2003) Karyotypic complexity of the NCI-60 drug-screening panel. Cancer Res 63:8634–8647

    PubMed  CAS  Google Scholar 

  27. Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, Wang YC, Duran GE, Sikic TL, Caldeira S, Skomedal H, Tu IP, Hernandez-Boussard T, Johnson SW, O’Dwyer PJ, Fero MJ, Kristensen GB, Borresen-Dale AL, Hastie T, Tibshirani R, van de Rijn M, Teng NN, Longacre TA, Botstein D, Brown PO, Sikic BI (2003) Gene expression patterns in ovarian carcinomas. Mol Biol Cell 14:4376–4386

    Article  PubMed  CAS  Google Scholar 

  28. Wang Y, Wu R, Cho KR, Shedden KA, Barder TJ, Lubman DM (2006) Classification of cancer cell lines using an automated two-dimensional liquid mapping method with hierarchical clustering techniques. Mol Cell Proteomics 5:43–52

    PubMed  Google Scholar 

  29. Buick RN, Pullano R, Trent JM (1985) Comparative properties of five human ovarian adenocarcinoma cell lines. Cancer Res 45:3668–3676

    PubMed  CAS  Google Scholar 

  30. Kelland LR, Jones M, Abel G, Valenti M, Gwynne J, Harrap KR (1992) Human ovarian-carcinoma cell lines and companion xenografts: a disease-oriented approach to new platinum anticancer drug discovery. Cancer Chemother Pharmacol 30:43–50

    Article  PubMed  CAS  Google Scholar 

  31. Budman DR, Calabro A, Kreis W (2001) In vitro effects of dexrazoxane (Zinecard) and classical acute leukemia therapy: time to consider expanded clinical trials? Leukemia 15:1517–1520

    Article  PubMed  CAS  Google Scholar 

  32. Budman DR, Calabro A, Wang LG, Liu XM, Stiel L, Adams LM, Kreis W (2000) Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Cancer Invest 18:695–701

    Article  PubMed  CAS  Google Scholar 

  33. Budman DR, Calabro A, Kreis W (1998) In vitro evaluation of synergism or antagonism with combinations of new cytotoxic agents. Anticancer Drugs 9:697–702

    Article  PubMed  CAS  Google Scholar 

  34. Novartis (2007) Clinical Development: LBH-589589A. Investigator’s Brochure

  35. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  36. Greco WR, Bravo G, Parsons JC (1995) The search for synergy: a critical review from a response surface perspective. Pharmacol Rev 47:331–385

    PubMed  CAS  Google Scholar 

  37. Kerbel RS (2003) Human tumor xenografts as predictive preclinical models for anticancer drug activity in humans: better than commonly perceived-but they can be improved. Cancer Biol Ther 2:S134–139

    PubMed  CAS  Google Scholar 

  38. Chou T-C (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Experimental Therapeutics, Don Monti Division of Oncology, Monter Cancer Center, North Shore Univ. Hospital - NYU, 450 Lakeville Road, Lake Success, NY, 11042, USA

    Daniel R. Budman, Anthony Calabro & Veena John

  2. Department of Biostatistics, Feinstein Institute, 350 Community Drive, Manhasset, NY, 11030, USA

    Julia Tai

Authors
  1. Daniel R. Budman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julia Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anthony Calabro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Veena John
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel R. Budman.

Additional information

Supported in part by the Donna Dennis Foundation, and NCI CA 35279

Rights and permissions

Reprints and permissions

About this article

Cite this article

Budman, D.R., Tai, J., Calabro, A. et al. The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines. Invest New Drugs 29, 1224–1229 (2011). https://doi.org/10.1007/s10637-010-9467-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-010-9467-6

Keywords

Search

Navigation