Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors.
It has been recently demonstrated that histone deacetylase inhibitors inhibit angiogenesis, but their mechanism of action has not been characterized well. In this study, we examined the in vitro and in vivo effects of FK228 [(E)-(1S,4S,10S,21R)-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], an HDAC inhibitor, on the expression of angiogenesis factors in FK228-sensitive PC-3 prostate and FK228-resistant ACHN renal cancer cells. FK228 suppressed the expression of VEGF mRNA in PC-3 cells, but not in ACHN cells. FK228 also suppressed the expression of basic fibroblast growth factor (bFGF) mRNA in both PC-3 and ACHN cells. Under conditions of hypoxia, FK228 suppressed the expression of VEGF mRNA without modulating the expression of hypoxia-inducible factor-1 alpha mRNA in PC-3 cells. FK228 induced the highest acetylation of histone H3 and H4 in the P2 region of the VEGF promoter, which includes the hypoxia-inducible factor-1 alpha binding site that plays an important role in regulating the expression of VEGF gene. Moreover, FK228 reduced the amount of VEGF and bFGF protein, and their mRNA levels in PC-3 xenograft implanted in nude mice, but did not reduce them in ACHN xenograft.


CONCLUSIONS
(i) FK228 showed a suppressive effect on the expression of angiogenesis factors, such as VEGF and bFGF, in PC-3 xenograft but not in ACHN xenograft, which suggests that the effect on the expression of angiogenesis factors is important for the antitumor efficacy of FK228; (ii) FK228 caused histone acetylation of the VEGF promoter regions, which may contribute to the suppression of VEGF gene expression.
Sasakawa
Yuka
Y
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. yuka_sasakawa@po.fujisawa.co.jp
Naoe
Yoshinori
Y
Noto
Takahisa
T
Inoue
Takeshi
T
Sasakawa
Tatsuya
T
Matsuo
Masahiko
M
Manda
Toshitaka
T
Mutoh
Seitaro
S
D000107:Acetylation / Q000187:drug effects; D043925:Angiogenesis Inducing Agents; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D047630:Depsipeptides; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D043925:Angiogenesis Inducing Agents; D000903:Antibiotics, Antineoplastic; D002843:Chromatin; D004268:DNA-Binding Proteins; D047630:Depsipeptides; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D056572:Histone Deacetylase Inhibitors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009687:Nuclear Proteins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C087123:romidepsin