PURPOSE: 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. CONCLUSION: Vorinostat has the capacity to elicit CRT exposure, suggesting its usefulness as immunogenic antitumour agent.
PURPOSE: 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. CONCLUSION:Vorinostat has the capacity to elicit CRT exposure, suggesting its usefulness as immunogenic antitumour agent.
Authors: Oliver Kepp; Laura Senovilla; Ilio Vitale; Erika Vacchelli; Sandy Adjemian; Patrizia Agostinis; Lionel Apetoh; Fernando Aranda; Vincenzo Barnaba; Norma Bloy; Laura Bracci; Karine Breckpot; David Brough; Aitziber Buqué; Maria G Castro; Mara Cirone; Maria I Colombo; Isabelle Cremer; Sandra Demaria; Luciana Dini; Aristides G Eliopoulos; Alberto Faggioni; Silvia C Formenti; Jitka Fučíková; Lucia Gabriele; Udo S Gaipl; Jérôme Galon; Abhishek Garg; François Ghiringhelli; Nathalia A Giese; Zong Sheng Guo; Akseli Hemminki; Martin Herrmann; James W Hodge; Stefan Holdenrieder; Jamie Honeychurch; Hong-Min Hu; Xing Huang; Tim M Illidge; Koji Kono; Mladen Korbelik; Dmitri V Krysko; Sherene Loi; Pedro R Lowenstein; Enrico Lugli; Yuting Ma; Frank Madeo; Angelo A Manfredi; Isabelle Martins; Domenico Mavilio; Laurie Menger; Nicolò Merendino; Michael Michaud; Gregoire Mignot; Karen L Mossman; Gabriele Multhoff; Rudolf Oehler; Fabio Palombo; Theocharis Panaretakis; Jonathan Pol; Enrico Proietti; Jean-Ehrland Ricci; Chiara Riganti; Patrizia Rovere-Querini; Anna Rubartelli; Antonella Sistigu; Mark J Smyth; Juergen Sonnemann; Radek Spisek; John Stagg; Abdul Qader Sukkurwala; Eric Tartour; Andrew Thorburn; Stephen H Thorne; Peter Vandenabeele; Francesca Velotti; Samuel T Workenhe; Haining Yang; Wei-Xing Zong; Laurence Zitvogel; Guido Kroemer; Lorenzo Galluzzi Journal: Oncoimmunology Date: 2014-12-13 Impact factor: 8.110