title: Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells.
abstract: Chemotherapeutic treatment with combinations of drugs is front-line therapy for many types of cancer. Combining drugs that target different signaling pathways often lessens adverse side-effects while increasing the efficacy of treatment and reducing patient morbidity. Histone deacetylase (HDAC) inhibitors represent a novel class of anti-neoplastic agents that act by promoting acetylation of core histones, leading in turn to the uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell survival, proliferation, differentiation, and apoptosis. A defined scheduling protocol is described by which HDAC inhibitors facilitate the cytotoxic effectiveness of cisplatin (CDDP) in the killing of carcinoma cells. An oral squamous cell carcinoma cell line (HSC-3) was treated with sodium butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) or MS-275 on the day of, the day before, or the day after addition of CDDP. The IC50 (48-h assay) value of 3.48 microg/ml CDDP could be lowered to 0.41 microg/ml CDDP when concurrently combined with an HDAC inhibitor (MS-275). The percentage of apoptosis by treatment with CDDP for 24 h, followed by NaB for an additional 24 h without washing was significantly greater than that observed in the reverse order. Depending on the time of addition of HDAC inhibitors, CDDP-treated cells displayed varying degrees of apoptotic responses, indicating the critical nature of timing in the use of HDAC inhibitors. Interestingly, experiments suggested that cells arrested at the G1/S checkpoint by CDDP were more sensitive to subsequent treatment with an HDAC inhibitor. Moreover, these events were associated with an enhancement of reactive oxygen species (ROS) generation and caspase-3 activation by HDAC inhibitors. They raise the possibility that combining these agents may represent a novel anti-neoplastic strategy.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sato
authors.forename: Maiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yoshitaro
authors.initials: Y
authors.lastname: Sato
authors.forename: Seishi
authors.initials: S
authors.lastname: Echigo
authors.forename: Hidemi
authors.initials: H
authors.lastname: Rikiishi
mesh_terms: D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009062:Mouth Neoplasms; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D018038:Sodium Selenite / Q000633:toxicity
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D018038:Sodium Selenite; D002945:Cisplatin