The synthetic atypical
retinoids containing an adamantyl group exhibit antiproliferative or proapoptotic activities. Apoptosis induction is a dose-dependent effect independent of
retinoid receptors. We have reported that induction of apoptosis by the atypical
retinoid,
ST1926, is associated with early manifestations of genotoxic stress. Indeed, in this study performed in ovarian
carcinoma cells, we show that exposure to
ST1926 resulted in an increase of early markers of DNA damage, including ATM and H2AX phosphorylation. In addition, we found that a novel
histone deacetylase (
HDAC) inhibitor (RC307) was able to enhance sensitivity of ovarian
carcinoma cells to
ST1926. Under conditions where single-agent treatment caused only antiproliferative effects, the combination of the atypical
retinoid and
HDAC inhibitor resulted in marked apoptotic cell death with a more rapid onset in wild-type p53 ovarian
carcinoma cells. The sensitization to ST1926-induced apoptosis was associated with an enhanced DNA damage response, because a prolonged expression of DNA damage markers (e.g., H2AX, p53 and RPA-2 phosphorylation) and a marked activation of DNA damage checkpoint
kinases (in particular, phosphorylation of Chk1) were observed indicating an accumulation of DNA damage by the
ST1926/
HDAC inhibitor combination. The study provides additional support to the role of DNA damage as a primary event leading to the activation of apoptosis in ovarian
carcinoma cells by adamantyl
retinoids and documents the potential therapeutic efficacy of the combination of
ST1926 and
HDAC inhibitors of the novel series.