Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells

Maiko Suzuki, Fumiaki Shinohara, Manabu Endo, Masaki Sugazaki, Seishi Echigo, Hidemi Rikiishi

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: During tumorigenesis, tumor suppressor and tumor-related genes are commonly silenced by aberrant DNA methylation in their promoter regions, which is one of the important determinants of susceptibility to 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) cells. Here, we examine the chemotherapeutic efficacy of epigenetic agents on 5-FU cytotoxicity. Method: We investigated the effect of a DNA methyltransferase (DNMT) inhibitor, zebularine (Zeb), on the chemosensitivity of 5-FU and cisplatin (CDDP) by MTT and TUNEL methods, and compared the molecular mechanism of action with those of a GSK3β inhibitor, LiCl, and an Hsp90 inhibitor, 17-AAG. Results: A significant apoptotic effect by a combination of Zeb or 17-AAG was found in CDDP treatment; however, considerable suppression of 5-FU-induced apoptosis was observed after incubation with Zeb, 17-AAG, or LiCl. Zeb's suppressive effects were associated with activation of the cAMP/PKA/CREB pathway, differing from mechanisms of 17-AAG and LiCl. Suppression of 5-FU-induced apoptosis by Zeb was not associated with increased Bcl-2 and Bcl-xL expressions dependent on transcription factor CREB, and with the expression level of thymidylate synthase. Conclusions: In the present study, we identified a more detailed mechanism of action by which Zeb suppresses 5-FU-induced apoptosis. These results indicate that combination therapies have to be carefully investigated due to potential harmful effects in the clinical application of DNMT inhibitors.

Original languageEnglish (US)
Pages (from-to)223-232
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume64
Issue number2
DOIs
StatePublished - Jul 1 2009

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pyrimidin-2-one beta-ribofuranoside
tanespimycin
Fluorouracil
Squamous Cell Carcinoma
Cells
Methyltransferases
Apoptosis
Tumors
Thymidylate Synthase
DNA
In Situ Nick-End Labeling
DNA Methylation
Cytotoxicity
Tumor Suppressor Genes
Genetic Promoter Regions
Epigenomics
Cisplatin
Epithelial Cells
Carcinogenesis
Transcription Factors

Keywords

  • 5-Fluorouracil
  • CAMP/PKA/CREB pathway
  • Chemosensitivity
  • Methylation
  • Suppressive action
  • Zebularine

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells. / Suzuki, Maiko; Shinohara, Fumiaki; Endo, Manabu; Sugazaki, Masaki; Echigo, Seishi; Rikiishi, Hidemi.

In: Cancer Chemotherapy and Pharmacology, Vol. 64, No. 2, 01.07.2009, p. 223-232.

Research output: Contribution to journalArticle

Suzuki, Maiko ; Shinohara, Fumiaki ; Endo, Manabu ; Sugazaki, Masaki ; Echigo, Seishi ; Rikiishi, Hidemi. / Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells. In: Cancer Chemotherapy and Pharmacology. 2009 ; Vol. 64, No. 2. pp. 223-232.
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AU - Shinohara, Fumiaki

AU - Endo, Manabu

AU - Sugazaki, Masaki

AU - Echigo, Seishi

AU - Rikiishi, Hidemi

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N2 - Purpose: During tumorigenesis, tumor suppressor and tumor-related genes are commonly silenced by aberrant DNA methylation in their promoter regions, which is one of the important determinants of susceptibility to 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) cells. Here, we examine the chemotherapeutic efficacy of epigenetic agents on 5-FU cytotoxicity. Method: We investigated the effect of a DNA methyltransferase (DNMT) inhibitor, zebularine (Zeb), on the chemosensitivity of 5-FU and cisplatin (CDDP) by MTT and TUNEL methods, and compared the molecular mechanism of action with those of a GSK3β inhibitor, LiCl, and an Hsp90 inhibitor, 17-AAG. Results: A significant apoptotic effect by a combination of Zeb or 17-AAG was found in CDDP treatment; however, considerable suppression of 5-FU-induced apoptosis was observed after incubation with Zeb, 17-AAG, or LiCl. Zeb's suppressive effects were associated with activation of the cAMP/PKA/CREB pathway, differing from mechanisms of 17-AAG and LiCl. Suppression of 5-FU-induced apoptosis by Zeb was not associated with increased Bcl-2 and Bcl-xL expressions dependent on transcription factor CREB, and with the expression level of thymidylate synthase. Conclusions: In the present study, we identified a more detailed mechanism of action by which Zeb suppresses 5-FU-induced apoptosis. These results indicate that combination therapies have to be carefully investigated due to potential harmful effects in the clinical application of DNMT inhibitors.

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