Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism

Abstract

The current paradigm stipulates that inhibition of histone deacetylase (HDAC) 6 is essential for the combinatorial effect of proteasome and HDAC inhibitors for the treatment of cancers. Our study aims to investigate the effect of combining different class I HDAC inhibitors (without HDAC6 action) with a proteasome inhibitor on apoptosis of nasopharyngeal carcinoma (NPC). We found that combination of a proteasome inhibitor, bortezomib, and several class I HDAC inhibitors, including MS-275, apicidin and romidepsin, potently induced killing of NPC cells both in vitro and in vivo. Among the drug pairs, combination of bortezomib and romidepsin (bort/romidepsin) was the most potent and could induce apoptosis at low nanomolar concentrations. The apoptosis of NPC cells was reactive oxygen species (ROS)-and caspase-dependent but was independent of HDAC6 inhibition. Of note, bort/romidepsin might directly suppress the formation of aggresome through the downregulation of c-myc. In addition, two markers of endoplasmic reticulum (ER) stress-induced apoptosis, ATF-4 and CHOP/GADD153, were upregulated, whereas a specific inhibitor of caspase-4 (an initiator of ER stress-induced apoptosis) could suppress the apoptosis. When ROS level in the NPC cells was reduced to the untreated level, ER stress-induced caspase activation was abrogated. Collectively, our data demonstrate a model of synergism between proteasome and class I HDAC inhibitors in the induction of ROS-dependent ER stress-induced apoptosis of NPC cells, independent of HDAC6 inhibition, and provide the rationale to combine the more specific and potent class I HDAC inhibitors with proteasome inhibitors for the treatment of cancers.

Combination of SAHA and bortezomib up‐regulates CDKN2A and CDKN1A and induces apoptosis of Epstein‐Barr virus‐positive Wp‐restricted Burkitt lymphoma and lymphoblastoid cell lines

“…HDAC inhibitors can synergize with proteasome inhibitors to up-regulate these tumour suppressor genes (Yu et al, 2003;Pei et al, 2004;Emanuele et al, 2007;Heider et al, 2009;Hui & Chiang, 2014). In this study, we hypothesized that combination of HDAC and proteasome inhibitors could synergistically induce apoptosis of Wp-restricted BL and LCL.…”

“…Our laboratory and others had previously reported that proteasome inhibitors, such as bortezomib, could potentiate the anti-tumour effect of HDAC inhibitors, such as SAHA, in various types of cancers (Emanuele et al, 2007;Miller et al, 2009;Zhang et al, 2009;Hui et al, 2013). Moreover, combination of HDAC and proteasome inhibitors can up-regulate tumour suppressor genes in different cancer cell lines (Yu et al, 2003;Pei et al, 2004;Emanuele et al, 2007;Heider et al, 2009;Hui & Chiang, 2014). Here, we demonstrated that SAHA/bortezomib could synergistically induce killing of Wp-restricted (Daudi and P3HR1-c16) or latency III (Raji and Mutu-III) BL cells but not latency I BL lines (Ak2003 and Mutu-I).…”

“…Synergism of SAHA and bortezomib was analysed with isobologram analysis and combination index (CI) calculation as described previously (Hui et al, 2013;Hui & Chiang, 2014). Curves that lie under the additive isobole in isobologram suggest synergism and vice versa.…”

“…HDAC inhibitors can also induce the expression of BCL2L11, CDKN2A and CDKN1A (Gui et al, 2004;Zhou et al, 2009). The induction of apoptosis and up-regulation of tumour suppressor genes by HDAC inhibitors can be greatly enhanced when co-administered with proteasome inhibitors, such as bortezomib (Yu et al, 2003;Pei et al, 2004;Emanuele et al, 2007;Heider et al, 2009;Hui & Chiang, 2014). However, it remains unknown whether combination of HDAC and proteasome inhibitors can affect the expression of tumour suppressor genes and induce apoptosis of EBV-associated B-cell malignancies.…”

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

“…Proteasome and histone deacetylase (HDAC) inhibitors have been postulated to block aggresome formations, thereby inhibiting the proliferation of malignant cells (3)(4)(5)(6)(7)(8). Recently, HDAC6-independent induction of apoptosis via ROS generation following treatment with proteasome and HDAC inhibitors was reported (9). However, it remains to be elucidated which pathogenetic molecules in MM cells would be targeted by this combination therapy.…”