The histone deacetylase inhibitor vorinostat induces calreticulin exposure in childhood brain tumour cells in vitro.
OBJECTIVE
It has recently been recognised that anticancer chemotherapy can elicit an immunogenic form of apoptosis characterised by the exposure of calreticulin (CRT) on the surface of dying tumour cells, entailing an immune response that contributes to the therapeutic outcome. CRT exposure has been found to be induced by anthracyclins and oxaliplatin, but not by other proapoptotic antineoplastic agents including etoposide, camptothecin and cisplatin. In this study, we examined the histone deacetylase inhibitor vorinostat for its capability to stimulate CRT exposure in tumour cells.


METHODS
Childhood tumour cells, i.e. the brain tumour cell lines PFSK and DAOY and the Ewing's sarcoma cell line CADO-ES-1, were treated with vorinostat, and CRT exposure was determined by flow cytometric analysis of CRT immunofluorescence. Combination effects of vorinostat/TRAIL and vorinostat/bortezomib were also assessed.


RESULTS
Vorinostat treatment induced CRT exposure in PFSK and DAOY cells, but not in caspase-8-deficient CADO-ES-1 cells. CRT exposure could be prevented by the pan-caspase inhibitor z-VAD-fmk and by brefeldin A, an inhibitor of Golgi-mediated transport.


CONCLUSIONS
Vorinostat has the capacity to elicit CRT exposure, suggesting its usefulness as immunogenic antitumour agent.
Sonnemann
Jürgen
J
Department of Paediatric Haematology and Oncology, University Children's Hospital Jena, Jena, Germany. juergen.sonnemann@med.uni-jena.de
Gressmann
Stephanie
S
Becker
Sabine
S
Wittig
Susan
S
Schmudde
Mareike
M
Beck
James F
JF
D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D037282:Calreticulin / Q000187:drug effects* / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique / Q000379:methods; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D000077337:Vorinostat
D000970:Antineoplastic Agents; D001897:Boronic Acids; D037282:Calreticulin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib; D053181:Caspase 8