Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism.
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.
Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong SAR, China.
Kwai Fung
KF
Hui
Alan K S
AK
Chiang
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001549:Benzamides / Q000737:chemistry; D001897:Boronic Acids / Q000737:chemistry; D000069286:Bortezomib; D002277:Carcinoma; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage; D047630:Depsipeptides / Q000737:chemistry; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D005260:Female; D005452:Fluoresceins / Q000737:chemistry; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D061988:Proteasome Inhibitors / Q000737:chemistry; D011719:Pyrazines / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D017382:Reactive Oxygen Species
D000970:Antineoplastic Agents; D001549:Benzamides; D001897:Boronic Acids; D047630:Depsipeptides; D005452:Fluoresceins; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011725:Pyridines; D017382:Reactive Oxygen Species; C102351:apicidin; C118739:entinostat; C029569:diacetyldichlorofluorescein; D000069286:Bortezomib; C087123:romidepsin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
class I histone deacetylase inhibitor; endoplasmic reticulum stress; histone deacetylase 6; nasopharyngeal carcinoma; proteasome inhibitor