Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells

Tomonori Sato, Maiko Suzuki, Yoshitaro Sato, Seishi Echigo, Hidemi Rikiishi

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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 μg/ml CDDP could be lowered to 0.41 μg/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.

Original languageEnglish (US)
Pages (from-to)1233-1241
Number of pages9
JournalInternational journal of oncology
Issue number5
StatePublished - May 2006
Externally publishedYes


  • Apoptosis
  • Cisplatin
  • Histone deacetylase inhibitor
  • Oral squamous cell carcinoma
  • Sequence-dependent

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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