Comparison of DNA demethylating and histone deacetylase inhibitors hydralazine-valproate versus vorinostat-decitabine incutaneous t-cell lymphoma in HUT78 cells

[摘要] Purpose: Cutaneous T-cell lymphoma (CTCL) is an uncommon extranodal non-Hodgkin T-cell lymphoma that originates from mature T lymphocytes homed at the skin. Epigenetic alterations observed in CTCL are not limited to overexpression of Histone Deacetylases but also to DNA hypermethylation. The known synergy between Histone deacetylase inhibitors (HDACi) and DNA methyltransferases inhibitors (DNMTi) suggests that combining these agent classes could be effective for CTCL. Methods: In this study, the combinations of the HDACi and DNMTi hydralazine/valproate (HV) and vorinostat/decitabine (VD) were compared in regard to viability inhibition, clonogenicity, pharmacological interaction and cell cycle effects in the CTCL cell line Hut78. In addition, the effect of these combinations was evaluated in normal peripheral blood mononuclear cells. Results: The results show that each of the DNMTi and HDACi exerts growth inhibition, mostly by inducing apoptosis as shown in the cell cycle distribution. However, in the combination of HV the interaction is more synergic and also it inhibits the clonogenic capacity of cells over time. Additionally, the HV combination seems to affect in a minor degree the viability of peripheral blood mononuclear cells. Conclusions: The results of this study and the preclinical and clinical evidence on the efficacy of combining HDACi with DNMTi strongly suggest that more studies are needed with this drug class combination in CTCL, particularly with the hydralazine-valproate scheme, which is safe, and these drugs are widely available and administered by oral route.

[学科分类] 血液学

[关键词] CTCL;HDACi;DNMTi;hydralazine;valproate;vorinostat;decitabine;synergy