Combined azacitidine and romidepsin enhances cytotoxicity in azacitidine-sensitive but not in azacitidine-resistant multiple myeloma cell lines.

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In hematopoietic tumor cells, aberrant epigenetic alterations of hypermethylation or histonedeacetylation are usually observed. In multiple myeloma （MM）, histone deacetylase inhibitors （HDIs）have proven anti-tumor activity, whereas the effects of DNA demethylating agents are obscure. In thisstudy, we examined the effect of DNA demethylating agent azacitidine and HDI romidepsin in humanMM cell lines RPMI8226 and U266. In RPMI8226 cells, azacitidine restored p16 expression accompaniedby disruption of its main target molecules DNA methyltransferases （DNMTs）, thereby showing antitumoreffect. However, in U266 cells, azacitidine-mediated demethylation was abrogated, thereby losingits anti-myeloma effect. The combination of azacitidine and romidepsin enhanced induction of apoptosisby activation of the caspase pathway in RPMI8226 cells but not in U266 cells. Furthermore, isobologramanalyses showed that this combination had an additive inhibitory effect on the growth of RPMI8226 cells,whereas in U266 cells it had a nearly subtractive effect. These results thus suggest that the combinationis effective in azacitidine-sensitive but not in azacitidine-resistant MM cells. Taken together, the resultssupport the utility of this combination as a potential therapy for MM； however, this therapy should beconsidered based on the sensitivity of the particular MM cells to azacitidine.
自治医科大学の論文