Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in cutaneous T cell lymphoma.
Proteasome inhibitors and histone deacetylase (HDAC) inhibitors are novel targeted therapies being evaluated in clinical trials for cutaneous T-cell lymphoma (CTCL). However, data in regard to tumor biology are limited with these agents. In the present study we analyzed the effects of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and the proteasome inhibitor bortezomib on human CTCL cells. Four CTCL cell lines (SeAx, Hut-78, MyLa, and HH) were exposed to bortezomib and/ or SAHA at different concentrations. Cell viability was quantified using the MTT assay. In addition, apoptosis and generation of reactive oxygen species were analyzed. Both agents potently inhibited cell viability and induced apoptosis. After 48 h of incubation, IC50 of bortezomib was noted at 8.3 nm, 7.9 nm, 6.3 nm, and 22.5 nm in SeAx, Hut-78, HH, and MyLa cells, respectively. For SAHA, the IC50 values were at 0.6 microm in SeAx cells, 0.75 microm in Hut-78 cells, 0.9 microm in HH cells, and 4.4 microm in MyLa cells. Importantly, combined treatment resulted in synergistic cytotoxic effects, as indicated by Combination indices values <1 using the median effect method of Chou and Talalay. We furthermore found that combined treatment with both agents lead to a decreased proteasome activity, an upregulation of the cell regulators p21 and p27 and increased expression of phosphorylated p38. In addition, we showed that SAHA reduced the vascular endothelial growth factor production of CTCL cells. Our results demonstrate that bortezomib and SAHA synergistically induce apoptosis in CTCL cells and thus provide a rationale for clinical trials of combined proteasome and histone deacetylase inhibition in the treatment of CTCL.
Heider
Ulrike
U
Department of Hematology and Oncology, Charité- Universitätsmedizin Berlin, Berlin, Germany.
Rademacher
Jessica
J
Lamottke
Britta
B
Mieth
Maren
M
Moebs
Markus
M
von Metzler
Ivana
I
Assaf
Chalid
C
Sezer
Orhan
O
D017209:Apoptosis; D001897:Boronic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy*; D010599:Pharmacokinetics; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000032:analysis; D000077337:Vorinostat
D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000077337:Vorinostat; D000069286:Bortezomib