Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid

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

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

In the present study, the precise mechanism of the enhancing action of histone deacetylase (HDAC) inhibitors on cisplatin (CDDP)-induced apoptosis was investigated using suberoylanilide hydroxamic acid (SAHA) in human oral squamous cell carcinoma cells (HSC-3). HDAC inhibitors are promising novel compounds for the treatment of cancer, which cooperate with chemotherapeutic agents to induce apoptosis. Apoptosis enhancement of HSC-3 cells by SAHA was accompanied by the activation of caspase-3, -8 and -9, suggesting a mitochondrial-dependent amplification loop. Concomitant treatment (CDDP/SAHA) of cells resulted in the most effective enhancement of apoptosis compared to other timing combinations. By means of cell-cycle synchronization, G0/G1-phase cells proved to be a more sensitive fraction to SAHA action than their synchronized counterparts in other phases. Furthermore, cells treated with SAHA revealed a decrease in intracellular reduced glutathione (GSH) contents. Of importance, the GSH synthesis inhibitor, diethyl maleate, decreased intracellular GSH and enhanced CDDP-induced apoptosis in a similar pattern of timing to SAHA. Thus, SAHA appears to disrupt the intracellular redox balance, which causes maximal apoptosis at the G0/G1 phase arrested by CDDP in HSC-3 cells. These results demonstrate that HDAC inhibitors not only cause a change in the histone acetylation status, but are also able to influence the apoptotic process at several levels, and GSH plays a key role in governing SAHA-dependent enhancement of CDDP-induced apoptosis.

Original languageEnglish
Pages (from-to)1181-1188
Number of pages8
JournalInternational journal of oncology
Volume30
Issue number5
DOIs
Publication statusPublished - 2007 May

Keywords

  • Apoptosis
  • Cell-cycle
  • Cisplatin
  • Glutathione
  • Oral squamous cell carcinoma
  • Suberoylanilide hydroxamic acid

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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