Trichostatin inhibits the growth of ACHN renal cell carcinoma cells via cell cycle arrest in association with p27, or apoptosis.
We investigated the in vitro effect of trichostatin (histone deacetylase inhibitor) on cell proliferation, cell cycle regulation and apoptosis in renal cell carcinoma cell lines. Trichostatin significantly inhibited the proliferation of all six cell lines examined in dose-dependent manner with IC50 of about 125-250 nM. Trichostatin (72-h incubation) induced a G1 phase arrest in ACHN, Caki-1, Caki-2 and Renca cell lines and a G2-M phase arrest in A498 cells. When we examined the effects of this drug on ACHN cells, trichostatin decreased the levels of CDK4, CDK6, cyclin D1 and cyclin A proteins. p27 protein was increased by trichostatin. In addition, trichostatin markedly enhanced the binding of p27 with CDK2 and CDK4. Furthermore, the activities of CDK2, CDK4- and CDK6-associated kinase were reduced and the lack of the CDK activity was paralleled by increased hypophosphorylation of Rb protein. Trichostatin also induced apoptosis in all the renal cell carcinoma cell lines. Apoptotic process of ACHN cells was associated with the changes of Bcl-2, caspase-9, caspase-3, caspase-7 proteins as well as mitochondria transmembrane potential (deltapsim) loss. Taken together, these results demonstrate that trichostatin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
Park
Woo Hyun
WH
Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jung
Chul Won
CW
Park
Joon Oh
JO
Kim
Kihyun
K
Kim
Won Seog
WS
Im
Young Hyuck
YH
Lee
Mark H
MH
Kang
Won Ki
WK
Park
Keunchil
K
D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D007680:Kidney Neoplasms / Q000473:pathology*; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins; D014407:Tumor Cells, Cultured
D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; C012589:trichostatin A; D018844:Cyclin-Dependent Kinases