Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell proliferation of human glioblastoma cells in vitro and in vivo.
We investigated the effects of FK228 on cell proliferation and apoptosis against human glioblastoma (GM) T98G, U251MG, and U87MG cells. Upon exposure to FK228, cell proliferation was inhibited, and apoptosis detected by the cleavage of CPP32 was induced. FK228 increased the expression levels of p21 (WAF-1) and of pro-apoptotic Bad protein in all GM cells. Furthermore, FK228 treatment also reduced the anti-apoptotic protein Bcl-xL in all GM cells and anti-apoptotic Bcl-2 in U87MG cells, thereby shifting the cellular equilibrium from life to death. An increased accumulation of histone H4 was detected in the p21 (WAF-1) promoter and the structural gene (exon 2) and the Bad structural gene (exon 2 and 3) upon treatment with FK228, as assessed by chromatin immunoprecipitation (ChIP) assay. Thus, the results indicated that an increased expression of p21 (WAF1) and Bad due to FK228 is regulated, at least in part, by the degree of acetylation of the gene-associated histone. We also found that FK228 inhibits cellular invasiveness and decreases MMP-2 activity. In addition, the growth of transplanted human GM m-3 cells into the subcutaneous tissue of hereditary athymic mice was significantly inhibited, and apoptosis was induced with FK228 treatment. The results suggested that FK228 might be useful in the treatment of human GM, although further studies will be needed.
Sawa
Hiroki
H
Oncology Research Center, Hokuto Hospital, Kisen 7-5, Inada-cho, 080-0833 Obihiro, Hokkaido, Japan. sawa@hokuto7.or.jp
Murakami
Hiromi
H
Kumagai
Masaoki
M
Nakasato
Matsuyoshi
M
Yamauchi
Shigeru
S
Matsuyama
Nozomu
N
Tamura
Yasuo
Y
Satone
Akira
A
Ide
Wataru
W
Hashimoto
Ikuo
I
Kamada
Hajime
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001973:Bromodeoxyuridine; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017690:Cell Transplantation / Q000379:methods; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D005091:Exons / Q000502:physiology; D005909:Glioblastoma / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013997:Time Factors; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
C494819:BAD protein, human; C494811:BCL2L1 protein, human; C494820:Bad protein, mouse; C494812:Bcl2l1 protein, mouse; C493956:CDKN1A protein, human; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C087123:romidepsin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020778:Matrix Metalloproteinase 2; D001973:Bromodeoxyuridine