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 journal › Article

53 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 (US)
Pages (from-to)1181-1188
Number of pages8
JournalInternational Journal of Oncology
Volume30
Issue number5
StatePublished - May 1 2007
Externally publishedYes

Fingerprint

Histone Deacetylase Inhibitors
Cisplatin
Squamous Cell Carcinoma
Apoptosis
Cell Cycle Resting Phase
diethyl maleate
G1 Phase
vorinostat
Caspase 8
Acetylation
Caspase 3
Histones
Oxidation-Reduction
Glutathione
Cell Cycle

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. / Rikiishi, Hidemi; Shinohara, Fumiaki; Sato, Tomonori; Sato, Yoshitaro; Suzuki, Maiko; Echigo, Seishi.

In: International Journal of Oncology, Vol. 30, No. 5, 01.05.2007, p. 1181-1188.

Research output: Contribution to journal › Article

Rikiishi, H, Shinohara, F, Sato, T, Sato, Y, Suzuki, M & Echigo, S 2007, 'Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid', International Journal of Oncology, vol. 30, no. 5, pp. 1181-1188.
Rikiishi H, Shinohara F, Sato T, Sato Y, Suzuki M, Echigo S. Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. International Journal of Oncology. 2007 May 1;30(5):1181-1188.
Rikiishi, Hidemi ; Shinohara, Fumiaki ; Sato, Tomonori ; Sato, Yoshitaro ; Suzuki, Maiko ; Echigo, Seishi. / Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. In: International Journal of Oncology. 2007 ; Vol. 30, No. 5. pp. 1181-1188.
@article{ff3d7aeac5b5498180ba8ff9cd3f22af,
title = "Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid",
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.",
keywords = "Apoptosis, Cell-cycle, Cisplatin, Glutathione, Oral squamous cell carcinoma, Suberoylanilide hydroxamic acid",
author = "Hidemi Rikiishi and Fumiaki Shinohara and Tomonori Sato and Yoshitaro Sato and Maiko Suzuki and Seishi Echigo",
year = "2007",
month = "5",
day = "1",
language = "English (US)",
volume = "30",
pages = "1181--1188",
journal = "International Journal of Oncology",
issn = "1019-6439",
publisher = "Spandidos Publications",
number = "5",

}

TY - JOUR

T1 - Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid

AU - Rikiishi, Hidemi

AU - Shinohara, Fumiaki

AU - Sato, Tomonori

AU - Sato, Yoshitaro

AU - Suzuki, Maiko

AU - Echigo, Seishi

PY - 2007/5/1

Y1 - 2007/5/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Cell-cycle

KW - Cisplatin

KW - Glutathione

KW - Oral squamous cell carcinoma

KW - Suberoylanilide hydroxamic acid

UR - http://www.scopus.com/inward/record.url?scp=34447315913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447315913&partnerID=8YFLogxK

M3 - Article

VL - 30

SP - 1181

EP - 1188

JO - International Journal of Oncology

JF - International Journal of Oncology

SN - 1019-6439

IS - 5

ER -

Access to Document