title: Treatment of nasopharyngeal carcinoma cells with the histone-deacetylase inhibitor abexinostat: cooperative effects with cis-platin and radiotherapy on patient-derived xenografts.
abstract: EBV-related nasopharyngeal carcinomas (NPCs) still raise serious therapeutic problems. The therapeutic potential of the histone-deacetylase (HDAC) inhibitor Abexinostat was investigated using 5 preclinical NPC models including 2 patient-derived xenografts (C15 and C17). The cytotoxicity of Abexinostat used either alone or in combination with cis-platin or irradiation was assessed in vitro by MTT and clonogenic assays using 2 EBV-negative (CNE1 and HONE1) and 3 EBV-positive NPC models (C15, C17 and C666-1). Subsequently, the 3 EBV-positive models were used under the form of xenografts to assess the impact of systemic treatments by Abexinostat or combinations of Abexinostat with cis-platin or irradiation. Several cell proteins known to be affected by HDAC inhibitors and the small viral non-coding RNA EBER1 were investigated in the treated tumors. Synergistic cytotoxic effects of Abexinostat combined with cis-platin or irradiation were demonstrated in vitro for each NPC model. When using xenografts, Abexinostat by itself (12.5 mg/kg, BID, 4 days a week for 3 weeks) had significant anti-tumor effects against C17. Cooperative effects with cis-platin (2 mg/kg, IP, at days 3, 10 and 17) and irradiation (1 Gy) were observed for the C15 and C17 xenografts. Simultaneously two types of biological alterations were induced in the tumor tissue, especially in the C17 model: a depletion of the DNA-repair protein RAD51 and a stronger in situ detection of the small viral RNA EBER1. Overall, these results support implementation of phase I/II clinical trials of Abexinostat for the treatment of NPC. A depletion of RAD51 is likely to contribute to the cooperation of Abexinostat with DNA damaging agents. Reduction of RAD51 combined to enhanced detection of EBER 1 might be helpful for early assessment of tumor response.
authors.affiliation: Université Paris-sud, CNRS-UMR 8126 and Gustave Roussy, Villejuif, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gressette
authors.affiliation: Université Paris-sud, CNRS-UMR 8126 and Gustave Roussy, Villejuif, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vérillaud
authors.affiliation: Université Paris-sud, CNRS-UMR 8126 and Gustave Roussy, Villejuif, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jimenez-Pailhès
authors.affiliation: Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Lelièvre
authors.affiliation: The Chinese University of Hong-Kong, Hong Kong SAR, China.
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.affiliation: Hôpital du Val de Grâce, Paris, France.
authors.forename: François-Régis
authors.initials: FR
authors.lastname: Ferrand
authors.affiliation: Université Paris-sud, CNRS-UMR 8126 and Gustave Roussy, Villejuif, France.
authors.forename: Charles-Henry
authors.initials: CH
authors.lastname: Gattolliat
authors.affiliation: Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Jacquet-Bescond
authors.affiliation: Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthier
authors.affiliation: Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.affiliation: Université Paris-sud, CNRS-UMR 8126 and Gustave Roussy, Villejuif, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology* / Q000633:toxicity; D002277:Carcinoma; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; C099537:Epstein-Barr virus encoded RNA 1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012367:RNA, Viral; D051135:Rad51 Recombinase; C512352:abexinostat; D002945:Cisplatin