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Investigational New Drugs
Published in: Investigational New Drugs 1/2007

01-02-2007 | Preclinical Studies

Cytotoxic effects of histone deacetylase inhibitor FK228 (depsipeptide, formally named FR901228) in combination with conventional anti-leukemia/lymphoma agents against human leukemia/lymphoma cell lines

Authors: Yasuhiko Kano, Miyuki Akutsu, Saburo Tsunoda, Tohru Izumi, Hiroyuki Kobayashi, Hiroyuki Mano, Yusuke Furukawa

Published in: Investigational New Drugs | Issue 1/2007

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Summary

FK228 is a novel antitumor depsipeptide that inhibits histone deacetylases and restores the expression of genes aberrantly suppressed in cancer cells. This agent was shown to have broad antitumor activity in preclinical studies, and is currently under phase I/II evaluations. Because of its wide spectrum of actions, it is reasonable to consider the combination with other anticancer drugs in clinical application. We studied the cytotoxic interaction of FK228 in combination with conventional antileukemic agents using human promyelocytic leukemia HL60, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia KU-812, T-cell lymphoblastic leukemia MOLT3 and Burkitt's lymphoma Raji cell lines. For the combination of FK228 and imatinib, Ph+ leukemia KU812, K562 and TCC-S cell lines were used. The cells were exposed simultaneously to FK228 and other agents for 4 days. Cell growth inhibition was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. We used the isobologram method of Steel and Peckham to evaluate the cytotoxic interaction at the concentration of drugs that produced 80% cell growth inhibition (IC80). FK228 showed an additive effect with cytarabine, carboplatin, doxorubicin, etoposide, 4-hydroperoxy-cyclophosphamide, 6-mercaptopurine and SN-38 (active metabolite of irinotecan) in all cell lines studied. FK228 with methotrexate and vincristine showed an antagonistic effect in three and one of the four cell lines, respectively. FK228 was additive with imatinib in all three Ph+ leukemia cells. Our findings suggest that FK228 is a promising candidate for combining with most anticancer agents except for methotrexate and vincristine, which produce suboptimal effects.
Literature
1.
Wolffe AP (1996) Histone deacetylase: a regulator of transcription. Science 272:371–372PubMed
2.
Kouzarides T (1999) Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet 9:40–48CrossRef
3.
Marks PA, Richon VM, Rifkind RA (2000) Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 92:1210–1216PubMedCrossRef
4.
Kramer OH, Gottlicher M, Heinzel T (2001) Histone deacetylase as a therapeutic target. Trends Endocrin Met 12:294–300CrossRef
5.
Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, Okuhara M (1994) FR901228 a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No 968 I Taxonomy fermentation isolation physico-chemical and biological properties and antitumor activity. J Antibiot 47:301–310PubMed
6.
Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S (1998) FR901228 a potent antitumor antibiotic is a novel histone deacetylase inhibitor. Exp Cell Res 241:126–133PubMedCrossRef
7.
Byrd JC, Shinn C, Ravi R, Willis CR, Waselenko JK, Flinn IW, Dawson NA, Grever MR (1999) Depsipeptide FR901228: a novel therapeutic agent with selective in vitro activity against human B-cell chronic lymphocytic leukemia cells. Blood 94:1401–1408PubMed
8.
Murata M, Towatari M, Kosugi H, Tanimoto M, Ueda R, Saito H, Naoe T (2000) Apoptotic cytotoxic effects of a histone deacetylase inhibitor FR901228 on malignant lymphoid cells. Jpn J Cancer Res 91:1154–1160PubMed
9.
Tsurutani J, Soda H, Oka M, Suenaga M, Doi S, Nakamura Y, Nakatomi K, Shiozawa K, Amada YY, Kamihira S, Kohno S (2003) Antiproliferative effects of the histone deacetylase inhibitor FR901228 on small-cell lung cancer lines and drug-resistant sublines. Int J Cancer 104:238–242PubMedCrossRef
10.
Ueda H, Manda T, Matsumoto S, Mukumoto S, Nishigaki F, Kawamura I, Shimomura K (1995) FR901228 a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No 968. III. Antitumor activities on experimental tumors in mice. J Antibiot 47:315–323
11.
Sasakawa Y, Naoe Y, Inoue T, Sasakawa T, Matsuo M, Manda T, Mutoh S (2002) Effects of FK228 a novel histone deacetylase inhibitor on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol 64:1079–1090PubMedCrossRef
12.
Piekarz RL, Robey R, Sandor V, Bakke S, Wilson WH, Dahmoush L, Kingma DM, Turner ML, Altemus R, Bates SE (2001) Inhibitor of histone deacetylation depsipeptide FR901228 in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood 98:2865–2868PubMedCrossRef
13.
Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J, Brooks R, Piekarz RL, Tucker E, Figg WD, Chan KK, Goldspiel B, Fojo AT, Balcerzak SP, Bates SE (2002) Phase I Trial of the Histone Deacetylase Inhibitor Depsipeptide FR901228 NSC630176 in Patients with Refractory Neoplasms. Clin Cancer Res 8:718–728PubMed
14.
Byrd JC, Marcucci G, Parthun MR, Xiao JJ, Klisovic RB, Moran M, Lin TS, Liu S, Sklenar AR, Davis ME, Lucas DM, Fischer B, Shank R, Tejaswi SL, Binkley P, Wright J, Chan KK, Grever MR (2005) A phase 1 and pharmacodynamic study of depsipeptide FK228 in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 105:959–967PubMedCrossRef
15.
Nishimura N, Furukawa Y, Sutheesophon K, Nakamura M, Kishi K, Okuda K, Sato Y, Kano Y (2003) Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c. Oncogene 22:4074–4082PubMedCrossRef
16.
Kano Y, Sakamoto S, Kasahara T, Akutsu M, Inoue Y, Miura Y (1991) In vitro effects of amsacrine in combination with other anti-cancer agents. Leukemia Res 15:1059–1066CrossRef
17.
Steel GG, Peckham MJ (1979) Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 5:85–93PubMed
18.
Kano Y, Ohnuma T, Okano T, Holland JF (1988) Effects of vincristine in combination with methotrexate and other antitumor agents in human acute lymphoblastic leukemia cells in culture. Cancer Res 48:351–356PubMed
19.
Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y (2001) In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood 97:1999–2007PubMedCrossRef
20.
Kano Y, Akutsu M, Tsunoda S, Suzuki K, Adachi K (1998) In vitro schedule-dependent interaction between paclitaxel and SN-38 the active metabolite of irinotecan in human carcinoma cell lines. Cancer Chemother Pharmacol 42:91–98PubMedCrossRef
21.
Sutheesophon K, Nishimura N, Kobayashi Y, Furukawa Y, Kawano M, Itoh K, Kano Y, Ishii H, Furukawa Y (2005) Involvement of the tumor necrosis factor TNF/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide FK228. J Cell Physiol 203:387–397PubMedCrossRef
22.
Sandor V, Senderowicz A, Mertins S, Sackett D, Sausville E, Blagosklonny MV, Bates SE (2000) P21-dependent G1 arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer 83:817–825PubMedCrossRef
23.
Kawano T, Horiguchi-Yamada J, Iwase S, Akiyama M, Furukawa Y, Kano Y, Yamada H (2004) Depsipeptide enhances imatinib mesylate-induced apoptosis of Bcr-Abl-positive cells and ectopic expression of cyclin D1, c-Myc or active MEK abrogates this effect. Anticancer Res 24:2705–2712PubMed
24.
Yu X, Guo ZS, Marcu MG, Neckers L, Nguyen DM, Chen GA, Schrump DS (2002) Modulation of p53 ErbB1 ErbB2 and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst 94:504–513PubMed
25.
Kobayashi Y, Ohtsuki M, Murakami T, Kobayashi T, Sutheesophon K, Kitayama H, Kano Y, Kusano E, Nakagawa H, Furukawa Y (2006) Histone deacetylase inhibitor FK228 suppresses the Ras-MAP kinase signaling pathway by upregulating Rap1 and induces apoptosis in malignant melanoma. Oncogene 25:512–524PubMed
26.
Aron JL, Parthun MR, Marcucci G, Kitada S, Mone AP, Davis ME, Shen T, Murphy T, Wickham J, Kanakry C, Lucas DM, Reed JC, Grever MR, Byrd JC (2003) Depsipeptide FR901228 induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase-8-mediated apoptosis and downregulation of c-FLIP protein. Blood 102:652–658PubMedCrossRef
27.
Sutheesophon K, Kobayashi Y, Takatoku M, Ozawa K, Kano Y, Ishii H, Furukawa Y (2006) Histone deacetylase inhibitor depsipeptide (FK228) induces apoptosis in leukemic cells by facilitating mitochondrial translocation of Bax, which is enhanced by proteasome inhibitor bortezomib. Acta Haematol 115:78–90PubMedCrossRef
28.
Blanchard F, Kinzie E, Wang Y, Duplomb L, Godard A, Held WA, Asch BB, Baumann H (2002) FR901228 an inhibitor of histone deacetylases increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins. Oncogene 21:6264–6277PubMedCrossRef
29.
Kwon HJ, Kim MS, Kim MJ, Nakajima H, Kim KW (2002) Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 97:290–296PubMedCrossRef
30.
Mie Lee Y, Kim SH, Kim HS, Jin Son M, Nakajima H, Jeong Kwon H, Kim KW (2003) Inhibition of hypoxia-induced angiogenesis by FK228 a specific histone deacetylase inhibitor via suppression of HIF-1alpha activity. Biochem Biophys Res Commun 300:241–246PubMedCrossRef
31.
Chu E, Allegra CJ (2000) Antifolates. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy. Lippincott-Raven, Philadelphia, pp 109–148
32.
Kitazono M, Bates S, Fok P, Fojo T, Blagosklonny MV (2002) The histone deacetylase inhibitor FR901228 (desipeptide restores expression and function of pseudo-null p53. Cancer Biol Ther 1:665–668PubMed
33.
Yu C, Rahmani M, Almenara J, Subler M, Krystal G, Conrad D, Varticovski L, Dent P, Grant S (2003) Histone Deacetylase Inhibitors Promote STI571-mediated Apoptosis in IMATINIB-sensitive and -resistant Bcr/Abl+ Human Myeloid Leukemia Cells. Cancer Res 63:2118–2126PubMed
34.
35.
Zhao L, Wientjes MG, Au JL (2004) Evaluation of combination chemotherapy: integration of nonlinear regression curve shift isobologram and combination index analyses. Clin Cancer Res 10:7994–8004PubMedCrossRef
Metadata
Title
Cytotoxic effects of histone deacetylase inhibitor FK228 (depsipeptide, formally named FR901228) in combination with conventional anti-leukemia/lymphoma agents against human leukemia/lymphoma cell lines
Authors
Yasuhiko Kano
Miyuki Akutsu
Saburo Tsunoda
Tohru Izumi
Hiroyuki Kobayashi
Hiroyuki Mano
Yusuke Furukawa
Publication date
01-02-2007
Published in
Investigational New Drugs / Issue 1/2007
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-006-9000-0

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