Partial resistence to entinostat and chidamide in doxorubicin-resistant human breast cancer MCF-7 cells

The benzaimides chidamide and entinostat are inhibitors of histone deacetylase and have been approved for clinic use. As drug resistance readily occurs in cancer chemotherapy, the characteristics of these drugs were studied in doxorubicin-sensitive and resistant human breast cancer MCF-7 cells. Using a CCK-8 assay for measuring cell proliferation, doxorubicin-resistant cells showed some resistance to chidamide and entinostat, with greater resistance to chidamide. Potentiation of cis-diamine-dichloroplatinum action by entinostat was observed in resistant cells. The accumulation of rhodomine 123, an indirect indicator of ATP-binding cassette B1 (ABCB1)-mediated resistance, was not affected by incubation with chidamide or entinostat, suggesting that neither drug is a substrate for ABCB1. However, ABCB1 expression was significantly increased in resistance cells incubated with a fixed concentration of entinostat. Slowing of the cell cycle at G1 phase and slightly increased cell numbers at G2/M phase was detected by flow cytometry when the cell lines were treated with chidamide or entinostat. Both drugs could induce spherical morphological changes and cleavage of PARP1, an indicater of apoptosis in doxorubicin-sensitive MCF-7 cells, whereas no apoptotic features were observed in resistant cells. These findings show that there is some resistance to chidamide and entinostat in doxorubicin-resistant MCF-7 cells and that this resistance may further oppose apoptosis.