Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma

Maiko Suzuki, Fumiaki Shinohara, Kentaro Nishimura, Seishi Echigo, Hidemi Rikiishi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Epigenetic alterations such as histone acetylation and DNA methylation play an important role in the regulation of gene expression for cell cycles and apoptosis that may affect the chemosensitivity of cancers. Previously, we have reported that the combination of suberoylanilide hydroxamic acid (SAHA), a newly developed histone deacetylase inhibitor, with cisplatin (CDDP) possessed synergistic cytotoxicity against human oral squamous cell carcinoma (OSCC) cell line HSC-3. In this study, we used a novel DNA methyltransferase inhibitor, zebularine (Zeb), to investigate the epigenetic influence on the sensitivity of carcinoma cell lines to 5-fluorouracil (5-FU) or CDDP by evaluating apoptotic inducibility. Treatment with CDDP or 5-FU either alone or in combination with Zeb or SAHA continued for 48 or 72 h. In HSC-3 cells, Zeb had chemosensitive efficacy with CDDP, but not 5-FU, whereas SAHA showed efficacy with both CDDP and 5-FU. We showed that Zeb has strong anti-proliferative activity against HSC-3 cells, shown by decreased cellular growth and G2/M cell cycle phase accumulation. Furthermore, DNA methylation could be a regulatory mechanism for dihydropyrimidine dehydrogenase (DPD), known to be a principal factor in 5-FU resistance. CDHP (5-chloro-2,4-dihydroxypyridine), an inhibitor of DPD, had an enhancing effect on the apoptotic ability of 5-FU alone or 5-FU/Zeb combination. In conclusion, the present study suggests that low-dose (IC 20) Zeb may sensitize cancer cells to CDDP, which may be an important characteristic for solid cancer treatment, and that DPD and other agents activated by Zeb in cancer cells could be an inhibitory factor in the response to apoptosis induced by 5-FU.

Original languageEnglish (US)
Pages (from-to)1449-1456
Number of pages8
JournalInternational Journal of Oncology
Volume31
Issue number6
StatePublished - Dec 1 2007
Externally publishedYes

Fingerprint

pyrimidin-2-one beta-ribofuranoside
Epigenomics
Fluorouracil
Cisplatin
Squamous Cell Carcinoma
Dihydrouracil Dehydrogenase (NADP)
DNA Methylation
Neoplasms
Cell Cycle
Apoptosis
Cell Line
Histone Deacetylase Inhibitors
Methyltransferases
Gene Expression Regulation
Acetylation

Keywords

  • 5-fluorouracil
  • Apoptosis
  • Cisplatin
  • Oral squamous cell carcinoma
  • SAHA
  • Zebularine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma. / Suzuki, Maiko; Shinohara, Fumiaki; Nishimura, Kentaro; Echigo, Seishi; Rikiishi, Hidemi.

In: International Journal of Oncology, Vol. 31, No. 6, 01.12.2007, p. 1449-1456.

Research output: Contribution to journalArticle

Suzuki, Maiko ; Shinohara, Fumiaki ; Nishimura, Kentaro ; Echigo, Seishi ; Rikiishi, Hidemi. / Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma. In: International Journal of Oncology. 2007 ; Vol. 31, No. 6. pp. 1449-1456.
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AU - Rikiishi, Hidemi

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