Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug

Abstract

In our quest to understand why dimethyl sulfoxide (DMSO) can cause growth arrest and terminal differentiation of transformed cells, we followed a path that led us to discover suberoylanilide hydroxamic acid (SAHA; vorinostat (Zolinza)), which is a histone deacetylase inhibitor. SAHA reacts with and blocks the catalytic site of these enzymes. Extensive structure-activity studies were done along the path from DMSO to SAHA. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in tumor-bearing animals at concentrations not toxic to normal cells. SAHA has many protein targets whose structure and function are altered by acetylation, including chromatin-associated histones, nonhistone gene transcription factors and proteins involved in regulation of cell proliferation, migration and death. In clinical trials, SAHA has shown significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application was approved by the US Food and Drug Administration for vorinostat for treatment of cutaneous T-cell lymphoma. More potent analogs of SAHA have shown unacceptable toxicity.

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References

  1. 1

    Marks, P. et al. Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer 1, 194–202 (2001).

  2. 2

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

  3. 3

    Marks, P.A. & Dokmanovic, M. Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin. Investig. Drugs 14, 1497–1511 (2005).

  4. 4

    Bolden, J.E., Peart, M.J. & Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769–784 (2006).

  5. 5

    Mitsiades, C.S. et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc. Natl. Acad. Sci. USA 101, 540–545 (2004).

  6. 6

    Peart, M.J. et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA 102, 3697–3702 (2005).

  7. 7

    Scott, G.K., Mattie, M.D., Berger, C.E., Benz, S.C. & Benz, C.C. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 66, 1277–1281 (2006).

  8. 8

    Rosato, R.R., Almenara, J.A., Dai, Y. & Grant, S. 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 (2003).

  9. 9

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

  10. 10

    Kelly, W.K. et al. Phase I study of the oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), in patients with advanced cancer. J. Clin. Oncol. 23, 3923–3931 (2005).

  11. 11

    O'Connor, O.A. et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J. Clin. Oncol. 24, 166–173 (2005).

  12. 12

    Marks, P.A., Rifkind, R.A., Richon, V.M. & Breslow, R. Inhibitors of histone deacetylase are potentially effective anticancer agents. Clin. Cancer Res. 7, 759–760 (2001).

  13. 13

    Bhalla, K.N. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J. Clin. Oncol. 23, 3971–3993 (2005).

  14. 14

    Monneret, C. Histone deacetylase inhibitors. Eur. J. Med. Chem. 40, 1–13 (2005).

  15. 15

    Hess-Stumpp, H. Histone deacetylase inhibitors and cancer: from cell biology to the clinic. Eur. J. Cell Biol. 84, 109–121 (2005).

  16. 16

    Moradei, O., Maroun, C.R., Paquin, I. & Vaisburg, A. Histone deacetylase inhibitors: latest developments, trends and prospects. Curr. Med. Chem. Anticancer Agents 5, 529–560 (2005).

  17. 17

    Peixoto, P. & Lansiaux, A. Histone-deacetylases inhibitors: from TSA to SAHA. Bull. Cancer 93, 27–36 (2006).

  18. 18

    Yoo, C.B. & Jones, P.A. Epigenetic therapy of cancer: past, present and future. Nat. Rev. Drug Discov. 5, 37–50 (2006).

  19. 19

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

  20. 20

    Friend, C., Scher, W., Holland, J.G. & Sato, T. 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 (1971).

  21. 21

    Bank, A. & Marks, P.A. Excess α chain synthesis relative to β chain synthesis in thalassemia major and minor. Nature 212, 1198–2000 (1966).

  22. 22

    Tanaka, M. et al. Induction of erythroid differentiation in murine virus infected eythroleukemia cells by highly polar compounds. Proc. Natl. Acad. Sci. USA 72, 1003–1006 (1975).

  23. 23

    Reuben, R.C., Wife, R.L., Breslow, R., Rifkind, R.A. & Marks, P.A. A new group of potent inducers of differentiation in murine erythroleukemia cells. Proc. Natl. Acad. Sci. USA 73, 862–866 (1976).

  24. 24

    Marks, P.A. & Rifkind, R.A. Erythroleukemic differentiation. Annu. Rev. Biochem. 47, 419–448 (1978).

  25. 25

    Marks, P.A., Sheffery, M. & Rifkind, R.A. Induction of transformed cells to terminal differentiation and the modulation of gene expression. Cancer Res. 47, 659–666 (1987).

  26. 26

    Richon, V.M., Ramsay, R.G., Rifkind, R.A. & Marks, P.A. Modulation of the c-myb, c-myc and p53 mRNA and protein levels during induced murine erythroleukemia cell differentiation. Oncogene 4, 165–173 (1989).

  27. 27

    Andreeff, M. et al. Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation-inducing agent. Blood 80, 2604–2609 (1992).

  28. 28

    Breslow, R. et al. Potent cytodifferentiating agents related to hexamethylenebisacetamide. Proc. Natl. Acad. Sci. USA 88, 5542–5546 (1991).

  29. 29

    Richon, V.M. et al. Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc. Natl. Acad. Sci. USA 93, 5705–5708 (1996).

  30. 30

    Meinke, P.T. & Liberator, P. Histone deacetylase: a target for antiproliferative and antiprotozoal agents. Curr. Med. Chem. 8, 211–235 (2001).

  31. 31

    Richon, V.M. et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl. Acad. Sci. USA 95, 3003–3007 (1998).

  32. 32

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

  33. 33

    Miller, T.A., Witter, D.J. & Belvedere, S. Histone deacetylase inhibitors. J. Med. Chem. 46, 5097–5116 (2003).

  34. 34

    Finnin, M.S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999).

  35. 35

    Drummond, D.C. et al. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu. Rev. Pharmacol. Toxicol. 45, 495–5280 (2005).

  36. 36

    Johnstone, R.W. & Licht, J.D. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4, 13–18 (2003).

  37. 37

    Guo, F. et al. Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res. 64, 2580–2589 (2004).

  38. 38

    Marks, P.A. & Jiang, X. Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle 4, 549–551 (2005).

  39. 39

    Ungerstedt, J.S. et al. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA 102, 673–678 (2005).

  40. 40

    Moradei, O., Maroun, C.R., Paquin, I. & Vaisburg, A. Histone deacetylase inhibitors: latest developments, trends and prospects. Curr. Med. Chem. Anticancer Agents 5, 529–560 (2005).

  41. 41

    Richon, V.M., Sandhoff, T.W., Rifkind, R.A. & Marks, P.A. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl. Acad. Sci. USA 97, 10014–10019 (2000).

  42. 42

    Butler, L.M. et al. 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 (2002).

  43. 43

    Gui, C.Y., Ngo, L., Xu, W.S., Richon, V.M. & Marks, P.A. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc. Natl. Acad. Sci. USA 101, 1241–1246 (2004).

  44. 44

    Butler, L.M. et al. 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 (2000).

  45. 45

    Yoshida, C. & Melo, J.V. Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. Int. J. Hematol. 79, 420–433 (2004).

  46. 46

    Fuino, L. et al. 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 (2003).

  47. 47

    Bali, P. et al. Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of her-2. Clin. Cancer Res. 11, 6382–6389 (2005).

  48. 48

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

  49. 49

    Kelly, W.K. et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res. 9, 3578–3588 (2003).

  50. 50

    Olsen, E. et al. Vorinostat (suberoylanilide hydroxamic acid, SAHA) is clinically active in advanced cutaneous T-cell lymphoma (CTCL): results of phase IIB trial. ASCO Annual Meeting Proceedings Part 1. (June 20 Suppl.) 24, 7500 (2006).

  51. 51

    Zhang, C., Richon, V., Ni, X., Talpur, R. & Duvic, M. Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J. Invest. Dermatol. 125, 1045–1052 (2005).

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Acknowledgements

The studies reviewed in this paper have been supported over the past 30 or more years by grants from the US National Institutes of Health, US National Science Foundation, Susan and Jack Rudin Foundation, David H. Koch Prostate Cancer Research Award, Robert J. and Helen C. Kleberg Foundation, DeWitt Wallace Fund for the MSKCC and the Japan Foundation for the Promotion of Cancer Research.

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Correspondence to Paul A Marks.

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Competing interests

Memorial Sloan-Kettering Cancer Center and Columbia University jointly hold patents on hydroxamic-based polar compounds, including SAHA, that were exclusively licensed to Aton Pharma Inc., a biotech company acquired by Merck, Inc. in April 2004. P.A.M. and R.B. were among the founders of Aton and have a financial interest in Merck’s further development of SAHA.

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Marks, P., Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 25, 84–90 (2007). https://doi.org/10.1038/nbt1272

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