Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells.
OBJECTIVE
To better understand the mechanisms of cytotoxicity and cell death induced by HDACI PCI-24781 in bone sarcoma cells.


METHODS
Four bone sarcoma cell lines were treated with PCI-24781, and the cytotoxicity was investigated. Further, accumulation of acetylated histones, p21, and PARP cleavage were evaluated in PCI-24781-treated cells. The synergistic effect of PCI-24781 to doxorubicin and its mechanism was investigated in bone sarcoma cells.


RESULTS
MTT assay demonstrated that the growth of bone sarcoma cells was inhibited after treatment with PCI-24781. Accumulation of acetylated histones, p21, and PARP cleavage were found in PCI-24781-treated cells. Expression of DNA repair protein RAD51 was inhibited, and the expression of apoptosis protein GADD45α was induced by PCI-24781 in bone sarcoma cells. Bone sarcoma cells treated with PCI-24781 become more sensitive to doxorubicin. The caspase-3/7 activity was increased with doxorubicin and PCI-24781 treatment in these cells.


CONCLUSIONS
HDACI PCI-24781 has a synergistic effect on doxorubicin-induced apoptosis in bone sarcoma cells.
Yang
Cao
C
Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Choy
Edwin
E
Hornicek
Francis J
FJ
Wood
Kirkham B
KB
Schwab
Joseph H
JH
Liu
Xianzhe
X
Mankin
Henry
H
Duan
Zhenfeng
Z
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002813:Chondrosarcoma / Q000188:drug therapy* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D000097642:GADD45 Proteins
D001572:Benzofurans; D020169:Caspases; D018797:Cell Cycle Proteins; D004317:Doxorubicin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D051135:Rad51 Recombinase; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C495153:RAD51 protein, human; C512352:abexinostat