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.

  • Original Article
  • Published:

Acute Leukemias

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

Leukemia volume 22, pages 2159–2168 (2008)Cite this article

Abstract

This study found that MS-275, a novel synthetic benzamide histone deacetylase inhibitor (HDACI), blocked Akt/mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) HL60 and acute promyelocytic leukemia (APL) NB4 cells, as assessed by decreased levels of the phosphorylated (p)-Akt, p-p70 ribosomal S6 kinase (p70S6K) and p-S6K by western blot analysis. Interestingly, further inactivation of mTOR by rapamycin analog RAD001 (everolimus) significantly enhanced MS-275-mediated growth inhibition and apoptosis of these cells in parallel with enhanced upregulation of p27kip1 and downregulation of c-Myc. In addition, RAD001 potentiated the ability of MS-275 to induce differentiation of HL60 and NB4 cells, as measured by the expression of CD11b cell surface antigens, as well as reduction of nitroblue tetrazolium. Importantly, RAD001 potentiated the ability of MS-275 to induce the expression of the myeloid differentiation-related transcription factor, CCAAT enhancer-binding protein-ɛ, in these cells in association with enhanced acetylation of histone H3 on its promoter. Furthermore, RAD001 (5 mg/kg) significantly enhanced the effects of MS-275 (10 mg/kg) to inhibit proliferation of HL60 tumor xenografts in nude mice without adverse effects. Taken together, concomitant administration of an HDACI and an mTOR inhibitor may be a promising treatment strategy for the individuals with a subset of human leukemia.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Lowenberg B, Downing JR, Burnet A . Acute myeloid leukemia. N Engl J Med 1999; 341: 1051–1062.

    Article  CAS  PubMed  Google Scholar 

  2. Wolff SN, Herzig RH, Fay JW, LeMaistre CF, Brown RA, Frei-Lahr D et al. High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: long-term follow-up and results. J Clin Oncol 1989; 7: 1260–1267.

    Article  CAS  PubMed  Google Scholar 

  3. Wells RJ, Woods WG, Buckley JD, Odom LF, Benjamin D, Bernstein I et al. Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study. J Clin Oncol 1994; 12: 2367–2377.

    Article  CAS  PubMed  Google Scholar 

  4. Harousseau JL, Cahn JY, Pignon B, Witz F, Milpied N, Delain M et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood 1997; 90: 2978–2986.

    CAS  PubMed  Google Scholar 

  5. Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L et al. German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Sakajiri S, Kumagai T, Kawamata N, Saitoh T, Said JW, Koeffler HP . Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines. Exp Hematol 2005; 33: 53–61.

    Article  CAS  PubMed  Google Scholar 

  8. Nishioka C, Ikezoe T, Yang J, Komatsu N, Bandobashi K, Taniguchi A et al. Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor kappaB. Leuk Res 2008; 32: 287–296.

    Article  CAS  PubMed  Google Scholar 

  9. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M et al. Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia. Nature 1998; 391: 815–818.

    Article  CAS  PubMed  Google Scholar 

  10. Grunstein M . Histone acetylation in chromatin structure and transcription. Nature 1997; 389: 349–352.

    Article  CAS  PubMed  Google Scholar 

  11. He LZ, Tolentino T, Grayson P, Zhong S, Warrell Jr RP, Rifkind RA et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 2001; 108: 1321–1330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gottlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001; 20: 6969–6978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kuendgen A, Gattermann N . Valproic acid for the treatment of myeloid malignancies. Cancer 2007; 110: 943–954.

    Article  CAS  PubMed  Google Scholar 

  14. Lekstrom-Himes J, Xanthopoulos KG . Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem 1998; 273: 28545–28548.

    Article  CAS  PubMed  Google Scholar 

  15. Chumakov AM, Grillier I, Chumakova E, Chih D, Slater J, Koeffler HP . Cloning of the novel human myeloid-cell-specific C/EBP-epsilon transcription factor. Mol Cell Biol 1997; 17: 1375–1386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morosetti R, Park DJ, Chumakov AM, Grillier I, Shiohara M, Gombart AF et al. A novel, myeloid transcription factor, C/EBP epsilon, is upregulated during granulocytic, but not monocytic, differentiation. Blood 1997; 90: 2591–2600.

    CAS  PubMed  Google Scholar 

  17. Yamanaka R, Barlow C, Lekstrom-Himes J, Liu PP, Eckhaus M, Decker T et al. Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice. Proc Natl Acad Sci USA 1997; 94: 13187–13192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nakajima H, Watanabe N, Shibata F, Kitamura T, Ikeda Y, Handa M . N-terminal region of CCAAT/enhancer-binding protein epsilon is critical for cell cycle arrest, apoptosis, and functional maturation during myeloid differentiation. J Biol Chem 2006; 281: 14494–14502.

    Article  CAS  PubMed  Google Scholar 

  19. Gery S, Gombart AF, Fung YK, Koeffler HP . C/EBPepsilon interacts with retinoblastoma and E2F1 during granulopoiesis. Blood 2004; 103: 828–835.

    Article  CAS  PubMed  Google Scholar 

  20. Bjornsti MA, Houghton PJ . Lost in translation: dysregulation of cap-dependent translation and cancer. Cancer Cell 2004; 5: 519–523.

    Article  CAS  PubMed  Google Scholar 

  21. Hay N, Sonenberg N . Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926–1945.

    Article  CAS  PubMed  Google Scholar 

  22. Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006; 12: 5165–5173.

    Article  CAS  PubMed  Google Scholar 

  23. Nishioka C, Ikezoe T, Yang J, Koeffler HP, Taguchi H . Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-kappaB signal pathway. Leukemia 2007; 21: 1044–1049.

    Article  CAS  PubMed  Google Scholar 

  24. Ikezoe T, Nishioka C, Tasaka T, Yang Y, Komatsu N, Togitani K et al. The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol Cancer Ther 2006; 5: 2522–2530.

    Article  CAS  PubMed  Google Scholar 

  25. Nishioka C, Ikezoe T, Takeshita A, Yang J, Tasaka T, Yang Y et al. ZD6474 induces growth arrest and apoptosis of human leukemia cells, which is enhanced by concomitant use of a novel MEK inhibitor, AZD6244. Leukemia 2007; 21: 1308–1310.

    Article  CAS  PubMed  Google Scholar 

  26. Ikezoe T, Daar ES, Hisatake J, Taguchi H, Koeffler HP . HIV-1 protease inhibitors decrease proliferation and induce differentiation of human myelocytic leukemia cells. Blood 2000; 96: 3553–3559.

    CAS  PubMed  Google Scholar 

  27. Ikezoe T, Hisatake Y, Takeuchi T, Ohtsuki Y, Yang Y, Said JW et al. HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res 2004; 64: 7426–7431.

    Article  CAS  PubMed  Google Scholar 

  28. Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A . Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21(waf1) promoter in acute myelogenous leukemia cell. Leukemia 2008; 22: 1449–1452.

    Article  CAS  PubMed  Google Scholar 

  29. Ikezoe T, Tanosaki S, Krug U, Liu B, Cohen P, Taguchi H et al. Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids in myeloid leukemia cells. Blood 2004; 104: 237–242.

    Article  CAS  PubMed  Google Scholar 

  30. Nagaki K, Talbert PB, Zhong CX, Dawe RK, Henikoff S, Jiang J . Chromatin immunoprecipitation reveals that the 180-bp satellite repeat is the key functional DNA element of Arabidopsis thaliana centromeres. Genetics 2003; 163: 1221–1225.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rosato RR, Almenara JA, Grant S . 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 2003; 63: 3637–3645.

    CAS  PubMed  Google Scholar 

  32. Lucas DM, Davis ME, Parthun MR, Mone AP, Kitada S, Cunningham KD et al. The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia 2004; 18: 1207–1214.

    Article  CAS  PubMed  Google Scholar 

  33. Kawamata N, Chen J, Koeffler HP . Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells. Blood 2007; 110: 2667–2673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen CS, Weng SC, Tseng PH, Lin HP, Chen CS . Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem 2005; 280: 38879–38887.

    Article  CAS  PubMed  Google Scholar 

  35. Ishida S, Shigemoto-Mogami Y, Shinozaki Y, Kagechika H, Shudo K, Ozawa S et al. Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol 2004; 68: 2177–2186.

    Article  CAS  PubMed  Google Scholar 

  36. Ozpolat B, Akar U, Steiner M, Zorrilla-Calancha I, Tirado-Gomez M, Colburn N et al. Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells. Mol Cancer Res 2007; 5: 95–108.

    Article  CAS  PubMed  Google Scholar 

  37. Gery S, Park DJ, Vuong PT, Virk RK, Muller CI, Hofmann WK et al. RTP801 is a novel retinoic acid-responsive gene associated with myeloid differentiation. Exp Hematol 2007; 35: 572–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Corradetti MN, Inoki K, Guan KL . The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J Biol Chem 2005; 280: 9769–9772.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Kanae Foundation for the Promotion of Medical Science and the Fund for Academic Research from Kochi University. HPK is supported by NIH grants, as well as, the Sheryl Weissberg Lymphoma Foundation and the Parker Hughes Trust.

CN is grateful for a JSPS Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science. Author contribution: Takayuki Ikezoe contributed to the concept and design, interpreted and analyzed the data and wrote the article. Chie Nishioka performed the experiments and wrote the article. Jing Yang performed the experiments. H Phillip Koeffler provided critical revision and intellectual content. Akihito Yokoyama provided important intellectual content and gave final approval.

Author information

Authors and Affiliations

  1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

    C Nishioka, T Ikezoe, J Yang & A Yokoyama

  2. Research Fellow of the Japanese Society for the Promotion of Science (JSPS), Chiyodaku, Tokyo, Japan

    C Nishioka

  3. Department of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

    H P Koeffler

Authors
  1. C Nishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Ikezoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H P Koeffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Ikezoe.

Additional information

Conflict of interest

The authors declare no competitive financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nishioka, C., Ikezoe, T., Yang, J. et al. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia 22, 2159–2168 (2008). https://doi.org/10.1038/leu.2008.243

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.243

Keywords

This article is cited by

Search

Advanced search

Quick links