Advertisement

Molecular Medicine

, Volume 21, Issue 1, pp 824–832 | Cite as

Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

  • YanGuo Kong
  • Gustavo A. Barisone
  • Ranjit S. Sidhu
  • Robert T. O’Donnell
  • Joseph M. Tuscano
Research Article

Abstract

Checkpoint kinase inhibition has been studied as a way of enhancing the effectiveness of DNA-damaging agents. More recently, histone deacetylase inhibitors have shown efficacy in several cancers, including non-Hodgkin lymphoma. To evaluate the effectiveness of this combination for the treatment of lymphoma, we examined the combination of AR42, a histone deacetylase inhibitor, and checkpoint kinase 2 (CHEK2) inhibitor II in vitro and in vivo. The combination resulted in up to 10-fold increase in potency in five Burkitt lymphoma cell lines when compared with either drug alone. Both drugs inhibited tumor progression in xenograft models, but the combination was more effective than either agent alone, resulting in regression of established tumors. No toxicity was observed. These results suggest that the combination of histone deacetylase inhibition and checkpoint kinase inhibition represent an effective and nontoxic treatment option that should be further explored in preclinical and clinical studies.

Notes

Acknowledgments

This work was supported by the Schwedler Family Foundation and the deLeuze Non-Toxic Cure for Lymphoma Fund.

References

  1. 1.
    Cheson BD, et al. (2007) Revised response criteria for malignant lymphoma. J. Clin. Oncol, 25:579–86.CrossRefGoogle Scholar
  2. 2.
    Greiner TC, Medeiros LJ, Jaffe ES. (1995) Non-Hodgkin’s lymphoma. Cancer. 75(1 Suppl):370–80.CrossRefGoogle Scholar
  3. 3.
    Shankland KR, Armitage JO, Hancock BW. (2012) Non-Hodgkin lymphoma. Lancet. 380:848–57.CrossRefGoogle Scholar
  4. 4.
    Bush ML, et al. (2011)AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. Neuro. Oncol. 13:983–99.CrossRefGoogle Scholar
  5. 5.
    Chen CS, et al. (2005) Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J. Biol. Chem. 280:38879–87.CrossRefGoogle Scholar
  6. 6.
    Jacob A, et al. (2012) Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas. Laryngoscope. 122:174–89.CrossRefGoogle Scholar
  7. 7.
    Lucas DM, et al. (2010) The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo. PLoS One. 5: e10941.CrossRefGoogle Scholar
  8. 8.
    Balch C, et al. (2012) A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells. Cancer Biol. Ther. 13:681–93.CrossRefGoogle Scholar
  9. 9.
    Sargeant AM, et al. (2008) OSU-HDAC42, a histone deacetylase inhibitor, blocks prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate model. Cancer Res. 68:3999–4009.CrossRefGoogle Scholar
  10. 10.
    Zimmerman B, et al. (2011) Efficacy of novel histone deacetylase inhibitor, AR42, in a mouse model of, human T-lymphotropic virus type 1 adult T cell lymphoma. Leuk. Res. 35:1491–7.CrossRefGoogle Scholar
  11. 11.
    Zhao WL, et al. (2007) Combined effects of histone deacetylase inhibitor and rituximab on non-Hodgkin’s B-lymphoma cells apoptosis. Exp. Hematol. 35:1801–11.CrossRefGoogle Scholar
  12. 12.
    Shimizu R, et al. (2010) HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells. Leukemia. 24:1760–8.CrossRefGoogle Scholar
  13. 13.
    Shi W, et al. (2012) Combined effect of histone deacetylase inhibitor suberoylanilide hydroxamic acid and anti-CD20 monoclonal antibody rituximab on mantle cell lymphoma cells apoptosis. Leuk. Res. 36:749–55.CrossRefGoogle Scholar
  14. 14.
    Kong Y, et al. (2014) Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7. Leuk. Res. 38:1320–26.CrossRefGoogle Scholar
  15. 15.
    Xu WS, Parmigiani RB, Marks PA. (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 26:5541–52.CrossRefGoogle Scholar
  16. 16.
    Minucci S, Pelicci PG. (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer. 6:38–51.CrossRefGoogle Scholar
  17. 17.
    Byrd JC, et al. (2005) A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood. 105:959–67.CrossRefGoogle Scholar
  18. 18.
    Sampath D, et al. (2012) Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood. 119:1162–72.CrossRefGoogle Scholar
  19. 19.
    Kulp SK, et al. (2006) Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clin. Cancer Res. 12:5199–206.CrossRefGoogle Scholar
  20. 20.
    Lu YS, et al. (2007) Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma. Hepatology. 46:1119–30.CrossRefGoogle Scholar
  21. 21.
    Pommier Y, et al. (2006) Chk2 molecular interaction map and rationale for Chk2 inhibitors. Clin. Cancer Res. 12:2657–61.CrossRefGoogle Scholar
  22. 22.
    Lovly CM, et al. (2008) Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379. Mol. Cell. Biol. 28:5874–85.CrossRefGoogle Scholar
  23. 23.
    Stolz A, et al. (2010) The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat. Cell. Biol. 12:492–9.CrossRefGoogle Scholar
  24. 24.
    Castedo M, et al. (2004) The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. Oncogene. 23:4353–61.CrossRefGoogle Scholar
  25. 25.
    Perona R, et al. (2008) Role of CHK2 in cancer development. Clin. Transl. Oncol. 10:538–42.CrossRefGoogle Scholar
  26. 26.
    Ferrao PT, et al. (2012) Efficacy of CHK inhibitors as single agents in MYC-driven lymphoma cells. Oncogene. 31:1661–72.CrossRefGoogle Scholar
  27. 27.
    Dai B, et al. (2011) Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma. Nat. Commun. 2:402.CrossRefGoogle Scholar
  28. 28.
    Chou TC, Martin N. (2005) CompuSyn for Drug Combinations and for General Dose-Effect Analysis. Paramus (NJ): ComboSyn, Inc. Available from: https://doi.org/www.combosyn.com/feature.html.Google Scholar
  29. 29.
    Chou TC, Talalay P. (1981) Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur. J. Biochem. 115:207–16.CrossRefGoogle Scholar
  30. 30.
    Cifone MA, Fidler IJ. (1980) Correlation of patterns of anchorage-independent growth with in vivo behavior of cells from a murine fibrosarcoma. Proc. Natl. Acad. Sci. U. S. A. 77:1039–43.CrossRefGoogle Scholar
  31. 31.
    Lucas DM, et al. (2004) The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia. 18:1207–14.CrossRefGoogle Scholar
  32. 32.
    Garrett MD, Collins I. (2011) Anticancer therapy with checkpoint inhibitors: what, where and when? Trends Pharmacol. Sci. 32:308–16.CrossRefGoogle Scholar
  33. 33.
    Ma CX, Janetka JW, Piwnica-Worms H. (2011) Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends Mol. Med. 17:88–96.CrossRefGoogle Scholar
  34. 34.
    Dai Y, Grant S. (2010) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin. Cancer Res. 16:376–83.CrossRefGoogle Scholar
  35. 35.
    Bucher N, Britten CD. (2008) G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. Br. J. Cancer. 98:523–8.CrossRefGoogle Scholar
  36. 36.
    Ma X, Ezzeldin HH, Diasio RB. (2009) Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs. 69:1911–34.CrossRefGoogle Scholar
  37. 37.
    Wang J, et al. (2013) Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol. Cancer Ther. 12:925–36.CrossRefGoogle Scholar
  38. 38.
    Lee CK, et al. (2010) HDAC inhibition synergistically enhances alkylator-induced DNA damage responses and apoptosis in multiple myeloma cells. Cancer Lett. 296:233–40.CrossRefGoogle Scholar
  39. 39.
    Sanchez E, et al. (2011) The histone deacetylase inhibitor LBH589 enhances the anti-myeloma effects of chemotherapy in vitro and in vivo. Leuk. Res. 35:373–9.CrossRefGoogle Scholar
  40. 40.
    Hildmann C, Riester D, Schwienhorst A. (2007) Histone deacetylases—an important class of cellular regulators with a variety of functions. Appl. Microbiol. Biotechnol. 75:487–97.CrossRefGoogle Scholar
  41. 41.
    Lin TY, et al. (2010) AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. Blood. 115:4217–25.CrossRefGoogle Scholar
  42. 42.
    Sasakawa Y, et al. (2003) Effects of FK228, a novel histone deacetylase inhibitor, on tumor growth and expression of p21 and c-myc genes in vivo. Cancer Lett. 195:161–8.CrossRefGoogle Scholar
  43. 43.
    Sasakawa Y, et al. (2002) Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem. Pharmacol. 64:1079–90.CrossRefGoogle Scholar
  44. 44.
    Yun HJ, et al. (2012) Widdrol activates DNA damage checkpoint through the signaling Chk2-p53-Cdc25A-p21-MCM4 pathway in HT29 cells. Mol. Cell. Biochem. 363:281–9.CrossRefGoogle Scholar
  45. 45.
    Wilson PM, et al. (2013) Sustained inhibition of deacetylases is required for the antitumor activity of the histone deactylase inhibitors panobinostat and vorinostat in models of colorectal cancer. Invest. New Drugs. 31:845–57.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • YanGuo Kong
    • 1
    • 2
  • Gustavo A. Barisone
    • 1
  • Ranjit S. Sidhu
    • 1
  • Robert T. O’Donnell
    • 1
    • 3
  • Joseph M. Tuscano
    • 1
    • 3
  1. 1.Division of Hematology and Oncology, Department of Internal MedicineUniversity of California Davis School of Medicine, Health SystemSacramentoUSA
  2. 2.Department of Neurosurgery, Peking University Medical College HospitalChinese Academy of Medical SciencesBeijingChina
  3. 3.Department of Veterans AffairsNorthern California Healthcare SystemSacramentoUSA

Personalised recommendations