Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Discovery and development of SAHA as an anticancer agent

Abstract

The path to the discovery of suberoylanilide hydroxamic acid (SAHA, vorinostat) began over three decades ago with our studies designed to understand why dimethylsulfoxide causes terminal differentiation of the virus-transformed cells, murine erythroleukemia cells. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in vivo at concentrations that have little or no toxic effects on normal cells. It was discovered that SAHA inhibits the activity of histone deacetylases (HDACs), including all 11 known human class I and class II HDACs. HDACs have many protein targets whose structure and function are altered by acetylation including histones and non-histone proteins component of transcription factors controlling gene expression and proteins that regulate cell proliferation, migration and death. SAHA is in clinical trials and has significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application has been approved for SAHA (vorinostat) treatment of cutaneous T-cell lymphoma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  • Andreeff M, Stone R, Michaeli J, Young CW, Tong WP, Sogoloff H et al. (1992). Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation-inducing agent. Blood 80: 2604–2609.

    CAS  PubMed  Google Scholar 

  • Arner ES, Holmgren A . (2000). Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267: 6102–6109.

    Article  CAS  PubMed  Google Scholar 

  • Bhalla KN . (2005). Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol 23: 3971–3993.

    Article  CAS  PubMed  Google Scholar 

  • Breslow R, Jursic B, Yan ZF, Friedman E, Leng L, Ngo L et al. (1991). Potent cytodifferentiating agents related to hexamethylene bisacetamide. Proc Natl Acad Sci USA 88: 5542–5546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C et al. (2000). Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60: 5165–5170.

    CAS  PubMed  Google Scholar 

  • Butler LM, Zhou X, Xu W-S, Scher HI, Rifkind RA, Marks PA et al. (2002). The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci USA 99: 11700–11705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dokmanovic M, Marks PA . (2005). Prospects: Histone deacetylase inhibitors. J Cell Biochem 96: 293–304.

    Article  CAS  PubMed  Google Scholar 

  • Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA et al. (1999). Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401: 188–193.

    Article  CAS  PubMed  Google Scholar 

  • Friend C, Scher W, Holland JG, Sato T . (1971). Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide. Proc Natl Acad Sci USA 68: 378–382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H et al. (2003). Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2: 971–984.

    CAS  PubMed  Google Scholar 

  • Gui CY, Ngo L, Xu WS, Richon VM, Marks PA . (2004). Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA 101: 1241–1246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haggerty TJ, Zeller KI, Osthus RC, Wonsey DR, Dang CV . (2003). A strategy for identifying transcription factor binding sites reveals two classes of genomic c-Myc target sites. Proc Natl Acad Sci USA 100: 5313–5318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hail Jr N . (2005). Mitochondria: a novel target for the chemoprevention of cancer. Apoptosis 10: 687–705.

    Article  CAS  PubMed  Google Scholar 

  • Hu E, Dul E, Sung CM, Chen Z, Kirkpatrick R, Zhang GF et al. (2003). Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther 307: 720–728.

    Article  CAS  PubMed  Google Scholar 

  • Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A et al. (2005). Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11: 71–76.

    Article  CAS  PubMed  Google Scholar 

  • Johnstone RW, Licht JD . (2003). Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4: 13–18.

    Article  CAS  PubMed  Google Scholar 

  • Kelly W, Marks P . (2005). Drug Insight: histone deacetylase inhibitors-development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clini Pract Oncol 2: 150–157.

    Article  CAS  Google Scholar 

  • Kelly WK, O'Connor OA, Krug L, Chiao J, Heaney M, Curley T et al. (2005). Phase I study of the oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), in patients with advanced cancer. J Clin Oncol 23: 3923–3931.

    Article  CAS  PubMed  Google Scholar 

  • Kelly WK, Richon VM, O'Connor O, Curley T, MacGregor-Curtelli B, Tong W et al. (2003). Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9: 3578–3588.

    CAS  PubMed  Google Scholar 

  • Lehrmann H, Pritchard LL, Harel-Bellan A . (2002). Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation. Adv Cancer Res 86: 41–65.

    Article  CAS  PubMed  Google Scholar 

  • Li LCL-C, Carroll PRPR, Dahiya RR . (2005a). Epigenetic changes in prostate cancer: implication for diagnosis and treatment. J Nat Cancer Instit 97: 103.

    Article  CAS  Google Scholar 

  • Li X, Wong C, Mysel R, Slobodov G, Metwalli A, Kruska J et al. (2005b). Screening and identification of differentially expressed transcripts in circulating cells of prostate cancer patients using suppression subtractive hybridization. Mol Cancer 4: 30.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mai A, Massa S, Pezzi R, Rotili D, Loidl P, Brosch G . (2003). Discovery of (aryloxopropenyl)pyrrolyl hydroxyamides as selective inhibitors of class IIa histone deacetylase homologue HD1-A. J Med Chem 46: 4826–4829.

    Article  CAS  PubMed  Google Scholar 

  • Mai A, Massa S, Pezzi R, Simeoni S, Rotili D, Nebbioso A et al. (2005). Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. J Med Chem 48: 3344–3353.

    Article  CAS  PubMed  Google Scholar 

  • Marks PA, Rifkind RA . (1978). Erythroleukemic differentiation. Annu Rev Biochem 47: 419–448.

    Article  CAS  PubMed  Google Scholar 

  • Marks PA, Sheffery M, Rifkind RA . (1987). Induction of transformed cells to terminal differentiation and the modulation of gene expression. Cancer Res 47: 659–666.

    CAS  PubMed  Google Scholar 

  • McEleny KR, Watson RW, Coffey RN, O'Neill AJ, Fitzpatrick JM . (2002). Inhibitors of apoptosis proteins in prostate cancer cell lines. Prostate 51: 133–140.

    Article  CAS  PubMed  Google Scholar 

  • Miller TA, Witter DJ, Belvedere S . (2003). Histone deacetylase inhibitors. J Med Chem 46: 5097–5116.

    Article  CAS  PubMed  Google Scholar 

  • Minucci S, Pelicci PG . (2006). Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6: 38–51.

    Article  CAS  PubMed  Google Scholar 

  • Olsen EO, Kim Y, Kuzel T, Pacheco T, Foss F, Parker S et al. (2006). Vorinostat (suberoylanilide hydroxamic acid, SAHA) is clinically active in advanced cutaneous T-cell lymphoma (CTCL): results of a phase IIb trial. Proceedings of the American Society for Clinical Oncology Abstract 7500. Vol. 24, No. 18S, June 20, 2006.

  • Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA et al. (2005). Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 102: 3697–3702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peart MJ, Tainton KM, Ruefli AA, Dear AE, Sedelies KA, O'Reilly LA et al. (2003). Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res 63: 4460–4471.

    CAS  PubMed  Google Scholar 

  • Powis G, Mustacich D, Coon A . (2000). The role of the redox protein thioredoxin in cell growth and cancer. Free Radic Biol Med 29: 312–322.

    Article  CAS  PubMed  Google Scholar 

  • Reuben RC, Wife RL, Breslow R, Rifkind RA, Marks PA . (1976). A new group of potent inducers of differentiation in murine erythroleukemia cells. Proc Natl Acad Sci USA 73: 862–866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA et al. (1998). A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA 95: 3003–3007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richon VM, Ramsay RG, Rifkind RA, Marks PA . (1989). Modulation of the c-myb, c-myc and p53 mRNA and protein levels during induced murine erythroleukemia cell differentiation. Oncogene 4: 165–173.

    CAS  PubMed  Google Scholar 

  • Richon VM, Sandhoff TW, Rifkind RA, Marks PA . (2000). Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 97: 10014–10019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richon VM, Webb Y, Merger R, Sheppard T, Jursic B, Ngo L et al. (1996). Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc Natl Acad Sci USA 93: 5705–5708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosato RR, Almenara JA, Dai Y, Grant S . (2003a). Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol Cancer Ther 2: 1273–1284.

    CAS  PubMed  Google Scholar 

  • Rosato RR, Almenara JA, Grant S . (2003b). The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res 63: 3637–3645.

    CAS  PubMed  Google Scholar 

  • Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC . (2006). Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res 66: 1277–1281.

    Article  CAS  PubMed  Google Scholar 

  • Shao Y, Gao Z, Marks PA, Jiang X . (2004). Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA 101: 18030–18035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smirnov DA, Zweitzig DR, Foulk BW, Miller MC, Doyle GV, Pienta KJ et al. (2005). Global gene expression profiling of circulating tumor cells. Cancer Res 65: 4993–4997.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka M, Levy J, Terada M, Breslow R, Rifkind RA, Marks PA . (1975). Induction of erythroid differentiation in murine virus infected eythroleukemia cells by highly polar compounds. Proc Natl Acad Sci USA 72: 1003–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ungerstedt JS, Sowa Y, Xu WS, Shao Y, Dokmanovic M, Perez G et al. (2005). Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci USA 102: 673–678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waghray A, Schober M, Feroze F, Yao F, Virgin J, Chen YQ . (2001). Identification of differentially expressed genes by serial analysis of gene expression in human prostate cancer. Cancer Res 61: 4283–4286.

    CAS  PubMed  Google Scholar 

  • Xu W, Ngo L, Perez G, Dokmanovic M, Marks PA . (2006). Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor. Proc Natl Acad Sci USA 103: 15540–15545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamanaka K, Rocchi P, Miyake H, Fazli L, Vessella B, Zangemeister-Wittke U et al. (2005). A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells. Mol Cancer Ther 4: 1689–1698.

    Article  CAS  PubMed  Google Scholar 

  • Yoo CB, Jones PA . (2006). Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5: 37–50.

    Article  CAS  PubMed  Google Scholar 

  • Yoshida M, Kijima M, Akita M, Beppu T . (1990). Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265: 17174–17179.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The studies reviewed in this paper have been supported by grants from the National Institutes of Health, Susan and Jack Rudin Foundation, David H Koch Prostate Cancer Research Award, DeWitt Wallace Research Fund for the MSKCC. MSKCC and Columbia University jointly hold patents on hydroxamic based polar compounds, including SAHA, that were exclusively licensed to Aton Pharma. Inc., a biotechnology company acquired by Merck, Inc. in April, 2004. PAM was a founder of Aton and has a financial interest in Merck's further development of SAHA (vorinostat).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P A Marks.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marks, P. Discovery and development of SAHA as an anticancer agent. Oncogene 26, 1351–1356 (2007). https://doi.org/10.1038/sj.onc.1210204

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210204

Keywords

This article is cited by

Search

Quick links