lithium-chloride and tanespimycin

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.. 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.

Topics: 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