TY - JOUR
T1 - Zebularine suppresses the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells
AU - Suzuki, Maiko
AU - Shinohara, Fumiaki
AU - Endo, Manabu
AU - Sugazaki, Masaki
AU - Echigo, Seishi
AU - Rikiishi, Hidemi
N1 - Funding Information:
Acknowledgments We thank Mr. D. Mrozek for editing the manuscript. This work was supported in part by Grant-in-Aids for ScientiWc Research (20659309) from the Japan Society for the Promotion of Science and (19791480 and 19791482) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
PY - 2009/7
Y1 - 2009/7
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.
AB - 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.
KW - 5-Fluorouracil
KW - CAMP/PKA/CREB pathway
KW - Chemosensitivity
KW - Methylation
KW - Suppressive action
KW - Zebularine
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U2 - 10.1007/s00280-008-0833-4
DO - 10.1007/s00280-008-0833-4
M3 - Article
C2 - 18830594
AN - SCOPUS:67349268981
SN - 0344-5704
VL - 64
SP - 223
EP - 232
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -