[Synergistic effects of proteasome inhibitor and histone deacetylase inhibitor on apoptosis and aggresome formation in T lymphoma cells].
The aim of the study was to explore the synergistic effect of the proteasome inhibitor bortezomib (bor) and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) on apoptosis of T lymphoma cell lines Jurkat and Hut78, and on the formation of aggresome. Jurkat and Hut78 cells were treated with bor (10 nmol/L) or bor (10 nmol/L) combined with SAHA (2 micromol/L) respectively. Cell growth inhibition was estimated by trypan blue dye exclusion test. Cell morphology was evaluated by light microscopy with Wright's staining of cytocentrifuge preparations. Cell apoptosis was analyzed by flow cytometry. Ultrastructure of cell apoptosis and aggresome were observed by transmission electron microscopy. The results showed that proliferation of both Jurkat and Hut78 cells was significantly inhibited in the bor+SAHA group, as compared with the control group and the bor alone group. Flow cytometric analysis confirmed that the percentage of apoptosis in Jurkat and Hut78 cells in the bor+SAHA group (41.8+/-4.7% and 72.7+/-11.7% respectively) was remarkably higher than those in the control group (3.6+/-1.3% and 7.0+/-1.9% respectively) and the bor alone group (6.3+/-2.3% and 18.7+/-9.2% respectively) (p<0.01). Ultrastructure examination revealed that typical aggresomes in cells could be observed in bor alone group. The combination of bor and SAHA diminished both the amount and density of aggresomes, or even eliminated them, accompanied by the increased rate of apoptosis. It is concluded that proteasome inhibitor combined with histone deacetylase inhibitor synergically induces T lymphoma cell apoptosis. Bortezomib stimulates the formation of aggresome, while SAHA destroys this aggresome structure, which may be one of the mechanisms underlying the enhancement of bortezomib-induced apoptosis.
National Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Department of Hematology, Shanghai Ruijin Hospital, Medical College of Shanghai Jiaotong University, Shanghai 200025, China.
Xiao-Xing
XX
Jiang
Qun-Ling
QL
Zhang
Xin-Yu
XY
Chen
Wei-Li
WL
Wu
Zhi-Xiang
ZX
Shen
Wei-Li
WL
Zhao
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*
D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib