Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in cutaneous T cell lymphoma

Abstract

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.

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…Further studies are needed to fully define the mechanisms of resistance to HDAC inhibition in CTCL [255,[279][280][281][282], enabling the development of rational therapeutic combinations incorporating HDAC inhibitors in CTCL [283,284].…”

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

“…It alters gene expression by histone acetylation and mediates various cellular effects, including cell differentiation, cell-cycle arrest, and apoptosis, in different cancer cell types (9)(10)(11)(12). Combination of bortezomib and SAHA (bortezomib/SAHA) was shown to be effective in the treatment of hematologic malignant cells such as multiple myeloma (13), mantle cell lymphoma (14), cutaneous T-cell lymphoma (15), and leukemia (16,17). Bortezomib/SAHA triggers apoptosis through caspase activation (14,(16)(17)(18) and ROS generation (13)(14)(15)(16)19) in various types of cancers.…”

Trends in the treatment of cutaneous T-cell lymphoma &ndash; critical evaluation and perspectives on vorinostat

“…For instance, vorinostat has demonstrated synergy with the proteasome inhibitor bortezomib in cells derived from CTCL, adult T-cell leukemia/ lymphoma, and B-cell leukemia/lymphoma patients. 26,67,68 In CTCL cells, the combination up-regulates p21 and p27, and activates p38 mitogen-activated protein kinase, an enzyme responsive to stress stimuli. 67 Notably, HDAC6 is a class II HDAC that has been shown to have a pro-survival role via promotion of both aggresomes and autophagosomes.…”

“…26,67,68 In CTCL cells, the combination up-regulates p21 and p27, and activates p38 mitogen-activated protein kinase, an enzyme responsive to stress stimuli. 67 Notably, HDAC6 is a class II HDAC that has been shown to have a pro-survival role via promotion of both aggresomes and autophagosomes. Inhibition of HDAC6 via vorinostat may in turn prevent bortezomib-induced aggresome production.…”