We have shown that WT-161, a
histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-
tumor activity in
multiple myeloma (MM) in preclinical models. However, its activity in other type of
cancers has not yet been shown. In this study, we further evaluated the
biologic sequelae of
WT161 in
breast cancer cell lines.
WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERα and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by
WT161 are not dependent on HDAC6 inhibition. Moreover
WT161 analog MAZ1793, which lacks HDAC inhibitory effect, similarly triggers cell line growth inhibition and downregulation of these receptors. We also confirm that
WT161 significantly inhibits in vivo MCF7 cell growth, associated with downregulation of ERα, in a murine xenograft model. Finally,
WT161 synergistically enhances
bortezomib-induced cytotoxicity, even in
bortezomib-resistant
breast cancer cells. Our results therefore provide the rationale to develop a novel class of therapeutic agents targeting growth pathways central to the pathogenesis of
breast cancer.