Acquired resistance to
tamoxifen (Tam) is a critical problem in
breast cancer therapy. Therefore, new potential strategies for Tam-resistant
breast cancer are needed recently. In this study, we synthesized a novel
histone deacetylase (
HDAC) inhibitor,
MHY218, for the development of potent inhibitors of HDAC and evaluated its
biological activities by monitoring the anticancer effects in Tam-resistant MCF-7 (TAMR/MCF-7) cells via in vitro and in vivo studies.
MHY218 significantly inhibited the proliferation of TAMR/MCF-7 cells in a dose-dependent manner. The total HDAC
enzyme activity was significantly inhibited, corresponding with inhibition of acetylated H3 and H4 expression in TAMR/MCF-7 cells. HDAC1, 4, and 6 expression levels were decreased in response to
MHY218 treatment. Cell cycle analysis indicated that
MHY218 induced G2/M phase cell cycle arrest. As expected, apoptotic cell death was observed in response to
MHY218 treatment. Interestingly, levels of
beclin-1 and LC3-II, the markers of autophagy, were increased in TAMR/MCF-7 cells treated with
MHY218. The efficacy of
MHY218 was also compared with that of SAHA in vivo in a xenograft model of nude mice bearing a TAMR/MCF-7 cells.
MHY218 (10 mg/kg, twice a week for 21 days) completely inhibited
tumor growth and
MHY218 markedly inhibited the expression of proliferative cell
nuclear antigen (
PCNA) in
tumor tissue. These results indicate that
MHY218 can induce
caspase-independent autophagic cell death rather than apoptotic cell death. The MHY218-induced autophagic cell death could be a new strategy in the treatment of Tam-resistant human
breast cancer.