Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo

• Published in: Biochemical pharmacology Vol. 64; no. 7; pp. 1079 - 1090
• Main Authors: Sasakawa, Yuka, Naoe, Yoshinori, Inoue, Takeshi, Sasakawa, Tatsuya, Matsuo, Masahiko, Manda, Toshitaka, Mutoh, Seitaro
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2002; Elsevier Science
• Subjects: Acetylation; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Apoptosis; Biological and medical sciences; Cell Cycle - drug effects; Cell Differentiation - drug effects; Chemotherapy; Cholecalciferol - pharmacology; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Cyclins - genetics; Depsipeptides; Disease Models, Animal; FK228; Gelsolin - biosynthesis; Gelsolin - genetics; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors; Histones - metabolism; Humans; Leukemia - pathology; Lymphoma; Lymphoma - drug therapy; Lymphoma - pathology; Medical sciences; Mice; Mice, SCID; Neoplasm Transplantation; Peptides, Cyclic; Pharmacology. Drug treatments; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; Tretinoin - pharmacology; U-937; U937 Cells; Xenograft Model Antitumor Assays; APL, acute promyelocytic leukemia; U-937; q-PCR, quantitative polymerase chain reaction; Lymphoma; vitamin D 3, 1α,25-dihydroxy-vitamin D 3; FK228; ChIP, chromatin immunoprecipitation; PE, phycoerythrin; Histone deacetylase inhibitor; ATRA, all- trans retinoic acid; HDAC, histone deacetylase; PTCL, peripheral T-cell lymphoma; TSA, trichostatin A; CTCL, cutaneous T-cell lymphoma; Antineoplastic agent; Human; Intraperitoneal administration; Rodentia; Enzyme inhibitor; Malignant hemopathy; In vitro; Biological activity; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Lymphoproliferative syndrome; Animal; Established cell line; Mechanism of action; Tumor cell
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(02)01261-3

FK228 [( E)-(1 S,4 S,10 S,21 R)-7-[( Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone; FR901228, depsipeptide] is a novel histone deacetylase inhibitor that shows therapeutic efficacy in Phase I trials of patients with malignant lymphoma. However, its mechanism of action has not been characterized. In this study, we examined the in vitro and in vivo effects of FK228 on human lymphoma U-937 cells. FK228 very strongly inhibited the growth of U-937 cells with an ic 50 value of 5.92 nM. In a scid mouse lymphoma model, mice treated with FK228 once or twice a week survived longer than control mice, with median survival times of 30.5 (0.56 mg/kg) and 33 days (0.32 mg/kg), respectively (vs. 20 days in control mice). Remarkably, 2 out of 12 mice treated with FK228 (0.56 mg/kg once or twice a week) survived past the observation period of 60 days. The apoptotic population of U-937 cells time-dependently increased to 37.7% after 48 hr of treatment with FK228. In addition, FK228 induced G1 and G2/M arrest and the differentiation of U-937 cells to the CD11b +/CD14 + phenotype. Expression of p21 WAF1/Cip1 and gelsolin mRNA increased up to 654- and 152-fold, respectively, after 24 hr of treatment with FK228. FK228 caused histone acetylation in p21 WAF1/Cip1 promoter regions, including the Sp1-binding sites. In conclusion, (i) FK228 prolonged the survival time of scid mice in a lymphoma model, and (ii) the beneficial effects of FK228 on human lymphoma may be exerted through the induction of apoptosis, cell cycle arrest, and differentiation via the modulation of gene expression by histone acetylation.