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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2001 May;92(5):529–536. doi: 10.1111/j.1349-7006.2001.tb01126.x

In vivo Effects of a Histone Deacetylase Inhibitor, FK228, on Human Acute Promyelocytic Leukemia in NOD/Shi‐scid/scid Mice

Hiroshi Kosugi 1, Masafumi Ito 2, Yukiya Yamamoto 3, Masayuki Towatari 1, Mamoru Ito 4, Ryuzo Ueda 5, Hidehiko Saito 1, Tomoki Naoe 3,✉
PMCID: PMC5926744  PMID: 11376562

Abstract

Histone acetylation and deacetylation are closely linked to transcriptional activation and repression, respectively. In acute promyelocytic leukemia (APL), histone deacetylase inhibitors (HDACIs) have a synergistic effect with all‐iraws retinoic acid (ATRA) in vitro to induce differentiation. Here we report in vitro and in vivo effects of a HDACI, FK228 (formerly FR901228 or depsipeptide), on the human APL cell line NB4. FK228 had a strong and irreversible cytotoxicity compared with another HDACI, trichostatin A. In vivo administration of ATRA or FK228 alone partly inhibited the growth of established tumors of NB4 subcutaneously transplanted in NOD/Shi‐scid/scid mice, and the combination was synergistically effective. Histopathological examination revealed that the combination induced apoptosis and differentiation as well as histone acetylation. Intravenous injection of NB4 in NOD/Shi‐scid/scid mice followed by combination treatment significantly prevented leukemia death, whereas single administration did not. These findings suggest that FK228 is a promising agent to enhance ATRA‐sensitivity in the treatment of APL.

Keywords: Acute promyelocytic leukemia, All‐trans retinoic acid, Differentiation, Histone deacetylase inhibitor, FK228

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Reference

  • 1.Warrell , R. P. , Jr. , de The , H. , Wang , Z. Y. and Degos , L . Acute promyelocytic leukemia . N. Engl. J. Med. , 329 , 177 – 189 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 2.Grignani , F. , Fagioli , M. , Alcalay , M. , Longo , L. , Pandolfi , P. P. , Donti , E. , Biondi , A. , Lo Coco , F. and Pelicci , P. G . Acute promyelocytic leukemia: from genetics to treatment . Blood , 83 , 10 – 25 ( 1994. ). [PubMed] [Google Scholar]
  • 3.Degos , L. , Dombret , H. , Chomienne , C. , Daniel , M. T. , Miclea , J. M. , Chastang , C. , Castaigne , S. and Fenaux , P . All‐trans retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia . Blood , 85 , 2643 – 2653 ( 1995. ). [PubMed] [Google Scholar]
  • 4.de The , H. , Chomienne , C. , Lanotte , M. , Degos , L. and Dejean , A . The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus . Nature , 347 , 558 – 561 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 5.Kakizuka , A. , Miller , W. H. , Jr. , Umesono , K. , Warrell , R. P. , Jr. , Frankel , S. R. , Murty , V. V. , Dmitrovsky , E. and Evans , R. M.Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML . Cell , 66 , 663 – 674 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 6.Grignani , F. , Ferrucci , P. F. , Testa , U. , Talamo , G. , Fagioli , M. , Alcalay , M. , Mencarelli , A. , Peschle , C. , Nicoletti , I. and Pelicci , P. G . The acute promyelocytic leukemia‐specific PML‐RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells . Cell , 74 , 423 – 431 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 7.Melnick , A. and Licht , J. D . Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia . Blood , 93 , 3167 – 3215 ( 1999. ). [PubMed] [Google Scholar]
  • 8.Shao , W. , Benedetti , L. , Lamph , W. W. , Nervi , C. and Miller , W. H. , Jr.A retinoid‐resistant acute promyelocytic leukemia subclone expresses a dominant negative PML‐RAR alpha mutation . Blood , 89 , 4282 – 4289 ( 1997. ). [PubMed] [Google Scholar]
  • 9.Yoshida , H. , Kitamura , K. , Tanaka , K. , Omura , S. , Miyazaki , T. , Hachiya , T. , Ohno , R. and Naoe , T . Accelerated degradation of PML‐retinoic acid receptor alpha (PML‐RARA) oncoprotein by all‐trans‐retinoic acid in acute promyelocytic leukemia: possible role of the protea‐some pathway . Cancer Res. , 56 , 2945 – 2948 ( 1996. ). [PubMed] [Google Scholar]
  • 10.Wolffe , A. P . Histone deacetylase: a regulator of transcription . Science , 272 , 371 – 372 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 11.Strahl , B. D. and Allis , C. D . The language of covalent histone modifications . Nature , 403 , 41 – 45 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 12.Chakravarti , D. , LaMorte , V. J. , Nelson , M. C. , Nakajima , T. , Schulman , I. G. , Juguilon , H. , Montminy , M. and Evans , R. M . Role of CBP/P300 in nuclear receptor signalling . Nature , 383 , 99 – 103 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 13.Horlein , A. J. , Naar , A. M. , Heinzel , T. , Torchia , J. , Gloss , B. , Kurokawa , R. , Ryan , A. , Kamei , Y. , Soderstrom , M. , Glass , C. K. and Rosenfeld , M. G . Ligand‐independent repression by the thyroid hormone receptor mediated by a nuclear receptor co‐repressor . Nature , 377 , 397 – 404 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14.Licht , J. D. , Chomienne , C. , Goy , A. , Chen , A. , Scott , A. A. , Head , D. R. , Michaux , J. L. , Wu , Y. , DeBlasio , A. and Miller , W. H. , Jr. . Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17) . Blood , 85 , 1083 – 1094 ( 1995. ). [PubMed] [Google Scholar]
  • 15.Collins , S. J . Acute promyelocytic leukemia: relieving repression induces remission . Blood , 91 , 2631 – 2633 ( 1998. ). [PubMed] [Google Scholar]
  • 16.He , L. Z. , Guidez , F. , Tribioli , C. , Peruzzi , D. , Ruthardt , M. , Zelent , A. and Pandolfi , P. P . Distinct interactions of PML‐RARalpha and PLZF‐RARalpha with co‐repressors determine differential responses to RA in APL . Nat. Genet. , 18 , 126 – 135 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 17.Lin , R. J. , Nagy , L. , Inoue , S. , Shao , W. , Miller , W. H. , Jr. and Evans , R. M . Role of the histone deacetylase complex in acute promyelocytic leukaemia . Nature , 391 , 811 – 814 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 18.Grignani , F. , de Matteis , S. , Nervi , C. , Tomassoni , L. , Gelmetti , V. , Cioce , M. , Fanelli , M. , Ruthardt , M. , Ferrara , F. F. , Zamir , I. , Seiser , C. , Lazar , M. A. , Minucci , S. and Pelicci , P. G. I.Fusion proteins of the retinoic acid receptor‐alpha recruit histone deacetylase in promyelocytic leukaemia . Nature , 391 , 815 – 818 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 19.Kosugi , H. , Towatari , M. , Hatano , S. , Kitamura , K. , Kiyoi , H. , Kinoshita , T. , Tanimoto , M. , Murate , T. , Kawashima , K. , Saito , H. and Naoe , T . Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti‐leukemia therapy . Leukemia , 13 , 1316 – 1324 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 20.Kitamura , K. , Hoshi , S. , Koike , M. , Kiyoi , H. , Saito , H. and Naoe , T . Histone deacetylase inhibitor but not arsenic tri‐oxide differentiates acute promyelocytic leukaemia cells with t(ll;17) in combination with all‐trans retinoic acid . Br. J. Haematol , 108 , 696 – 702 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 21.Yoshida , M. , Nomura , S. and Beppu , T . Effects of tricho‐statins on differentiation of murine erythroleukemia cells . Cancer Res. , 47 , 3688 – 3691 ( 1987. ). [PubMed] [Google Scholar]
  • 22.Yoshida , M. and Beppu , T . Reversible arrest of proliferation of rat 3Y1 fibroblasts in both the Gl and G2 phases by trichostatin A . Exp. Cell Res. , 177 , 122 – 131 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 23.Medina , V. , Edmonds , B. , Young , G. P. , James , R. , Appleton , S. and Zalewski , P. D.Induction of caspase‐3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c‐dependent pathway . Cancer Res. , 57 , 3697 – 3707 ( 1997. ). [PubMed] [Google Scholar]
  • 24.Warrell , R. P. , Jr. , He , L. Z. , Richon , V. , Calleja , E. and Pandolfi , P. P . Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase . J. Natl. Cancer Inst. , 90 , 1621 – 1625 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 25.Ueda , H. , Manda , T. , Matsumoto , S. , Mukumoto , S. , Nishigaki , F. , Kawamura , I. and Shimomura , K . FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice . J. Antibiot. (Tokyo) , 47 , 315 – 323 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 26.Nakajima , H. , Kim , Y. B. , Terano , H. , Yoshida , M. and Horinouchi , S . FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor . Exp. Cell Res. , 241 , 126 – 133 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 27.Marshall , J. L. , Dahut , W. L. , Rizvi , N. , Wainer , I. W. , Chassaing , C. , Figuierra , M. and Hawkins , M. J . Phase I trial and pharmacokinetic (PK) analysis of depsipeptide in patients with advanced cancer . Proc. of Assoc., 35th Annu. Meet . ( 1998. ). [Google Scholar]
  • 28.Bates , S. E. , Sandor , V. , Bakke , S. , Chico , I. , Tucker , E. , Robey , R. , Sackett , D. , Chan , K. , Kang , M. , Figg , W. D. , Sauaville , E. , Balcerzak , S. and Fojo , T . A phase I study of FR901228 (Depsipeptide), a histone deacetylase inhibitor . Proc. of Assoc., 36th Annu. Meet . ( 1999. ). [Google Scholar]
  • 29.Kitamura , K. , Kiyoi , H. , Yoshida , H. , Saito , H. , Ohno , R. and Naoe , T . Mutant AF‐2 domain of PML‐RARa in reti‐noic acid‐resistant NB4 cells: differentiation induced by RA is triggered directly through PML‐RARa and its down‐regulation in acute promyelocytic leukemia . Leukemia , 11 , 1950 – 1956 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 30.Chan , K. K. , Bakhtiar , R. and Jiang , C . Depsipeptide (FR901228, NSC‐630176) pharmacokinetics in the rat by LC/MS/MS . Invest. New Drugs , 15 , 195 – 206 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 31.Chassaing , C. , Marshall , J. L. and Wainer , I. W . Determination of the antitumor agent depsipeptide in plasma by liquid chromatography on serial octadecyl stationary phases . J. Chromatogr. Sci. , 719 , 169 – 176 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 32.Yoshida , M. , Kijima , M. , Akita , M. and 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. ). [PubMed] [Google Scholar]
  • 33.Marks , P. A. , Richon , V. M. and Rifkind , R. A . Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells . J. Natl. Cancer Inst. , 92 , 1210 – 1216 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 34.Kijima , M. , Yoshida , M. , Sugita , K. , Horinouchi , S . and Beppu , T. Trapoxin , an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase . J. Biol. Chem. , 268 , 22429 – 22435 ( 1993. ). [PubMed] [Google Scholar]
  • 35.Kwon , H. J. , Owa , T. , Hassig , C. A. , Shimada , J. and Schreiber , S. L . Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase . Proc. Natl. Acad. Sci. USA , 95 , 3356 – 3361 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kim , Y. B. , Lee , K. H. , Sugita , K. , Yoshida , M. and Horinouchi , S . Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase . Oncogene , 18 , 2461 – 2470 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 37.Saito , A. , Yamashita , T. , Mariko , Y. , Nosaka , Y. , Tsuchiya , K. , Ando , T. , Suzuki , T. , Tsuruo , T. and Nakanishi , O . A synthetic inhibitor of histone deacetylase, MS‐27‐275, with marked in vivo antitumor activity against human tumors . Proc. Natl. Acad. Set. USA , 96 , 4592 – 4597 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Finnin , M. S. , Donigian , J. R. , Cohen , A. , Richon , V. M. , Rifkind , R. A. , Marks , P. A. , Breslow , R. and Pavletich , N. P . Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors . Nature , 401 , 188 – 193 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 39.Grozinger , C. M. , Hassig , C. A. and Schreiber , S. L . Three proteins define a class of human histone deacetylases related to yeast Hdalp . Proc. Natl. Acad. Sci. USA , 96 , 4868 – 4873 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Gu , W. and Roeder , R. G . Activation of p53 sequence‐specific DNA binding by acetylation of the p53 C‐terminal domain . Cell , 90 , 595 – 606 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 41.Zhang , S. Y. , Zhu , J. , Chen , G. Q. , Du , X. X. , Lu , L. J. , Zhang , Z. , Zhong , H. J. , Chen , H. R. , Wang , Z. Y. , Berger , R. , Lanotte , M. , Waxman , S. , Chen , Z. and Chen , S. J . Establishment of a human acute promyelocytic leukemia‐ascites model in SCID mice . Blood , 87 , 3404 – 3409 ( 1996. ). [PubMed] [Google Scholar]
  • 42.He , L. Z. , Tribioli , C. , Rivi , R. , Peruzzi , D. , Pelicci , P. G. , Scares , V. , Cattoretti , G. and Pandolfi , P. P . Acute leukemia with promyelocytic features in PML/RARα transgenic mice . Proc. Natl. Acad. Sci. USA , 94 , 5302 – 5307 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

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