Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines

The
synthesis and biological evaluation of potent hydroxamate-based
dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea
connecting unit linker region are described. The biological studies
included the evaluation of antiproliferative effects and HDAC inhibitory
activity in the human ovarian cancer cell line A2780, the human squamous
carcinoma cell line Cal27, and their cisplatin resistant sublines
A2780CisR and Cal27CisR. The three most potent compounds 1g–i showed IC50 values in the low μM
and sub-μM range. 1g–i revealed
low nM IC50 values for HDAC6 with up to 15-fold preference
over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold
selectivity
over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity
was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation
of 1g–i significantly enhanced the
antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g–i interacted synergistically with cisplatin.
These effects were more pronounced for the cisplatin resistant subline
Cal27CisR.