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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Adjuvants, Immunologic, Antimetabolites, Antineoplastic, Antineoplastic Agents, Apoptosis, Benzoquinones, Blotting, Western, Carcinoma, Squamous Cell, Cell Line, Tumor, Cisplatin, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Cytidine, DNA (Cytosine-5-)-Methyltransferases, Fluorouracil, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, HSP90 Heat-Shock Proteins, Humans, In Situ Nick-End Labeling, Lactams, Macrocyclic, Lithium Chloride, Mouth Neoplasms, NF-kappa B, Phosphorylation, Proto-Oncogene Proteins c-bcl-2, Signal Transduction.
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Does zebularine suppress the apoptotic potential of 5-fluorouracil via cAMP/PKA/CREB pathway against human oral squamous cell carcinoma cells? Context: 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. 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 GSK3beta inhibitor, LiCl, and an Hsp90 inhibitor, 17-AAG. 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.
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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. Final Decision: yes