Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells.
Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on osteosarcoama cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of a HDAC inhibitor Trichostatin A (TSA)-induced apoptosis in a osteosarcoma cell line HOS. We observed that TSA treatment decreased the viability of the cells and prominently increased acetylation of histone H3. Evidence was obtained indicating that TSA induced apoptosis of HOS cells as follows: (1) Generation of DNA fragmentation; (2) activation of procaspase-3; (3) cleavage of PARP; and (4) increase of DNA hypoploidy. The reduction of MMP and the release of cytochrome c to cytosol were also shown, indicating that TSA induces apoptosis in HOS cells in a histone acetylation- and mitochondria-dependent fashions. We also examined whether TSA can sensitize HOS cells to the action of an antitumor agent genistein. The combination therapy of TSA and genistein showed synergistic anticancer effect indicating that TSA can be considered as a novel therapeutic strategy for osteosarcoma not only from its direct apoptosis-inducing activity but also from the possibility of sensitization to other antitumor agents.
Roh
M S
MS
Institute of Cell Death and Differentiation, Dong-A University College of Medicine (BK21 program) and Medical Science Research Center, Busan 602-714, South Korea.
Kim
C W
CW
Park
B S
BS
Kim
G C
GC
Jeong
J H
JH
Kwon
H C
HC
Suh
D J
DJ
Cho
K H
KH
Yee
S-B
SB
Yoo
Y H
YH
D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000473:pathology*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D012516:Osteosarcoma / Q000473:pathology*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A