Abstract 4702: Antitumor activity of a novel histone deacetylase inhibitor S78454 in EBV-associated nasopharyngeal carcinoma

Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is the third leading cause of virus-related human malignancy. On average, NPCs are more radiosensitive and chemosensitive than other head and neck tumors. However, local relapse and distant organ metastases still raise serious therapeutic problems. Histone deacetylase (HDAC) inhibitors have recently emerged as a class of therapeutic agent for the treatment of both hematologic malignancies and solid tumors. In the present study, we investigated the antitumor effects of the novel Pan HDAC inhibitor S78454 in 3 NPC cell lines, namely C666-1 (EBV-positive NPC cell line), HONE1 and CNE1 (EBV-negative). The antiproliferative effects of S78454, used either alone or in combination with cis-platinum or irradiation, were evaluated using MTT assays and clonogenic assays. Combined treatment of S78454 with cis-platinum resulted in a synergistic inhibitory effect on cell proliferation, as well as on cell clonogenic growth. HDAC inhibition also enhanced radiosensitivity of NPC cell lines. Western blot detection of PARP cleavage revealed that the antiproliferative effects of S78454 were only partially related to apoptosis. Western blot analysis was also used to explore molecular mechanisms involved in cellular response to S78454. Quantitative assessment of tubulin acetylation confirmed that S78454 effectively increased protein acetylation, even at low concentrations. As previously reported in other tumors, RAD51 protein levels were significantly decreased after 48H of treatment, suggesting that HDAC inhibitors act, at least in part, by targeting homologous recombination. However, HDAC inhibitor-induced cell death involves not only epigenetic pathways, but numerous other mechanisms, through acetylation of a variety of non-histone and non-chromatin-associated proteins. For instance, the proteasome activity may play a role in the response to HDAC inhibitors, and the amount of HR23B - a carrier protein functionally related to the proteasome - has been identified as a determinant of HDAC inhibitors sensitivity. We found that HR23B protein levels were high in all 3 NPC cell lines. Nevertheless, there was a decrease in HR23B protein levels after treatment with S78454. Altogether, these results demonstrate that the novel HDAC inhibitor S78454, currently in Phase I/II clinical trials for the treatment of solid tumors and hematologic malignancies, has promising antitumour activity in NPC, especially in association with cis-platinum and ionizing radiation, ie the two most widely used antitumor agents in NPC. Experiments are in progress to assess the anti-tumor activity of S78454 on other types of NPC cells, including xenografted NPC tumor lines. The influence of the HDAC inhibitor on the regulation of EBV latency is also under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4702. doi:1538-7445.AM2012-4702