Zebularine-induced myeloma cell death is accompanied by decreased c-Myc expression.

PURPOSE: Epigenetic therapies have proven to be clinically effective in several hematological malignancies. Here, we aimed to evaluate the effect of a second-generation DNA demethylation agent, zebularine, on multiple myeloma (MM). METHODS: Western blot, ELISA, qRT-PCR, proliferation assays and cell transfection were used to investigate the mechanism of action of zebularine in MM. RESULTS: We found that zebularine induced apoptosis and DNA demethylation in most of the MM cell lines tested. Its cytotoxic effect was associated with a time-dependent decrease in the level of c-Myc protein. Moreover, zebularine induced H2AX phosphorylation, a surrogate marker of DNA damage, in five out of eight MM cell lines tested. CONCLUSIONS: Our study revealed novel effects of zebularine on MM that may have potential implications for DNA methylation-based therapies.