Hydrazide-Based Class I Selective HDAC Inhibitors Completely Reverse Chemoresistance Synergistically in Platinum-Resistant Solid Cancer Cells

In this work, we have synthesized a set of peptoid-based
histone
deacetylase inhibitors (HDACi) with a substituted hydrazide moiety
as zinc-binding group. Subsequently, all compounds were evaluated
in biochemical HDAC inhibition assays and for their antiproliferative
activity against native and cisplatin-resistant cancer cell lines.
The hydrazide derivatives with a propyl or butyl substituent (compounds 5 and 6) emerged as the most potent class I HDAC
selective inhibitors (HDAC1–3). Further, compounds 5 and 6 outperformed entinostat in cytotoxicity assays
and were able to reverse chemoresistance in cisplatin-resistant A2780
(ovarian) and Cal27 (head-neck) cancer cell lines. Moreover, the hydrazide
derivatives 5 and 6 showed strong synergism
with cisplatin (combination indices <0.2), again outperforming
entinostat, and increased DNA damage, p21, and pro-apoptotic BIM expression,
leading to caspase-mediated apoptosis and cell death. Thus, compounds 5 and 6 represent promising lead structures for
developing new HDACi capable of reversing chemoresistance in cisplatin
resistant cancer cells.