Experimental Hematology
Volume 38, Issue 8 , Pages 666-676 , August 2010

Inhibition of mTORC1 by RAD001 (everolimus) potentiates the effects of 1,25-dihydroxyvitamin D3 to induce growth arrest and differentiation of AML cells in vitro and in vivo

  • Jing Yang

      Affiliations

    • Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    • ,
  • Takayuki Ikezoe

      Affiliations

    • Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    • Corresponding Author InformationOffprint requests to: Takayuki Ikezoe, M.D., Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan
    • ,
  • Chie Nishioka

      Affiliations

    • Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    • ,
  • Lei Ni

      Affiliations

    • Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    • ,
  • H. Phillip Koeffler

      Affiliations

    • Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, Calif., USA
    • ,
  • Akihito Yokoyama

      Affiliations

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

Received 25 December 2009 ,Revised 8 March 2010 ,Accepted 30 March 2010.

References 

  1. Takashi K, Lee YS, Hughes SV, et al. 19-Nor-1,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. Cancer Res. 2005;65:2489–2497
  2. Colstone KW, Chander SK, Mackay AG, Coombes RC. Effects of synthetic vitamin D analogues on breast cancer cell proliferation in vitro and in vivo. Biochemical Pharm. 1992;44:693–702
  3. Shabahang M, Buras RR, Davoodi F, Schumaker LM, Nauta RJ, Evans SRT. 1,25-Dihydroxyvitamin D3 receptor as a marker of human colon carcinoma cell line differentiation and growth inhibition. Cancer Res. 1993;53:3712–3718
  4. Eisman JA, Barkla DH, Tutton PJM. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res. 1987;47:21–25
  5. Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP. Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev. 1996;10:142–153
  6. Rots NY, Iavarone A, Bromleigh V, Freedman LP. Induced differentiation of U937 cells by 1,25-dihydroxyvitamin D3 involves cell cycle arrest in G1 that is preceded by a transient proliferative burst and an increase in cyclin expression. Blood. 1999;93:2721–2729
  7. Elstner E, Campbell MJ, Munker R, et al. Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells. Prostate. 1999;40:141–149
  8. Muto A, Kizaki M, Yamato K, et al. 1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid-resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1). Blood. 1999;93:2225–2233
  9. Munker R, Kobayashi T, Elstner E, et al. A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia. Blood. 1996;88:2201–2209
  10. Wang JR, Zhao Y, Kauss MA, Spindel S, Lian H. Akt regulates vitamin D3-induced leukemia cell functional differentiation via Raf/MEK/ERK MAPK signaling. Eur J Cell Biol. 2009;88:103–115
  11. O'Kelly J, Uskokovic M, Lemp N, Vadgama J, Koeffler HP. Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the Akt/mTOR signaling pathway. J Steroid Biochem Mol Biol. 2000;100:107–116
  12. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Nat Rev Cancer. 2002;2:489–501
  13. Inoki K, Li K, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol. 2002;4:648–657
  14. Bjornsti MA, Houghton PJ. Lost in translation: dysregulation of cap-dependent translation and cancer. Cancer Cell. 2004;5:519–523
  15. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–1945
  16. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122–1128
  17. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14:1296–1302
  18. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–1101
  19. Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia. 2008;22:2159–2168
  20. Nishioka C, Ikezoe T, Yang J, Gery S, Koeffler HP, Yokoyama A. Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells. Int J Cancer. 2009;125:1710–1720
  21. Chan S. Targeting the mammalian target of rapamycin(mTOR): a new approach to treating cancer. Br J Cancer. 2004;91:1420–1424
  22. Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ, Koeffler HP. Antiproliferative activity of RAD001(everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia. 2007;21:333–339
  23. Munker P, Kobayashi T, Elstner E, et al. A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia. Blood. 1996;88:2201–2209
  24. Ikezoe T, Nishioka C, Tasaka T, 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
  25. Ikezoe T, Tanosaki S, Krug U, et al. Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids in myeloid leukemia cells. Blood. 2004;104:237–242
  26. 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
  27. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A. 2000;97:10014–10019
  28. Nishio H, Walsh MJ. CCAAT displacement protein/cut homolog recruits G9a histone lysine methyltransferase to repress transcription. Proc Natl Acad Sci U S A. 2004;101:11257–11262
  29. 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
  30. Ikezoe T, Yang Y, Bandobashi K, et al. Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-kappa B signal pathways. Mol Cancer Ther. 2005;4:578–586
  31. Archer SY, Hodin RA. Histone acetylation and cancer. Curr Opin Genet Dev. 1999;9:171–174
  32. Pepper C, Thomas A, Hoy A, Milligan D, Bentley P, Fegan C. The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. Blood. 2003;101:24554–24560
  33. Hickish T, Cunningham D, Colston K, et al. The effect of 1,25-dihydroxyvitamin D3 on lymphoma cell lines and expression of the vitamin D receptor in lymphoma. Br J Cancer. 1993;68:668–672
  34. Koeffler HP, Aslanian N, O'Kelly J. Vitamin D2 analog (Paricalcitol; Zemplar) for treatment of myelodysplastic syndrome. Leukemia Res. 2005;29:1259–1262
  35. Amir E, Simmons CE, Freedman OC, et al. A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases. Cancer. 2010;116:284–291
  36. Wietrzyk J, Nevozhay D, Filip B, Milczarek M, Kutner A. The antitumor effect of lowered doses of cytostatics combined with new analogs of vitamin D in mice. Anticancer Res. 2007;27:3387–3398
  37. Chiang KC, Persons KS, Istfan NW, Holick MF, Chen TC. Fish oil enhances the antiproliferative effect of 1alpha, 25-dihydroxyvitamin D3 on liver cancer cells. Anticancer Res. 2009;29:3591–3596
  38. Park SJ, Kim M, Kim NH, et al. Auranofin promotes retinoic acid- or dihydroxyvitamin D3-mediated cell differentiation of promyelocytic leukaemia cells by increasing histone acetylation. Br J Pharmacol. 2008;154:1196–1205
  39. Marderosian M, Sharma A, Funk AP, et al. Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling. Oncogene. 2006;25:6277–6290
  40. Gregory MA, Qi Y, Hann SR. Phosphorylation by glycogen sythase kinase-3 controls c-Myc proteolysis and subnuclear localization. J Biol Chem. 2003;278:51606–51612
  41. Gera JF, Mellingghoff IK, Shi Y, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-Myc expression. J Biol Chem. 2004;279:2737–2746
  42. Wall M, Poortinga G, Hannan KM, Pearson RB, Hannan RD, McArthur GA. Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation. Blood. 2008;112:2305–2317
  43. Polek TC, Stewart LV, Ryu EJ, Cohen MB, Allegretto EA, Weigel NL. p53 is required for 1,25-dihydroxyvitamin D3-inducedG0 arrest but is not required for G1 accumulation or apoptosis of LNCaP prostate cancer cells. Endocrinology. 2003;144:50–60
  44. Malone JM, Deppe G. Inhibition of c- myc in breast and ovarian carcinoma cells by 1, 25-dihydroxyvitamin D3, retinoic acid and dexamethasone. Anticancer Drugs. 1993;4:201–208
  45. Tong WM, Kallay E, Hofer H, et al. Growth regulation of human colon cancer cells by epidermal growth factor and 1, 25-dihydroxyvitamin D3 is mediated by mutual modulation of receptor expression. Eur J Cancer. 1998;34:2119–2125
  46. Yee KW, Zeng Z, Konopleva M, 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
  47. Zent CS, Laplant BR, Johnston PB, et al. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer. 2010;116:2201–2207

PII: S0301-472X(10)00136-0

doi: 10.1016/j.exphem.2010.03.020

Experimental Hematology
Volume 38, Issue 8 , Pages 666-676 , August 2010

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