Antitumor effects of (S)-HDAC42, a phenylbutyrate-derived histone deacetylase inhibitor, in multiple myeloma cells

Abstract

Epigenetic agents are among the newly targeted therapeutic strategies being studied with intense interest for patients with multiple myeloma. Here, we demonstrate the antitumor activity of a phenylbutyrate-based histone deacetylase (HDAC) inhibitor, (S)-HDAC42, and identify its possible targets in myeloma cells. The antiproliferative effect of (S)-HDAC42 was compared with suberoylanilide hydroxamic acid (SAHA) in three myeloma cell lines, IM-9, RPMI-8226, and U266. Flow cytometry and terminal transferase dUTP nick-end labeling (TUNEL) assay were used to demonstrate the induction of apoptosis by (S)-HDAC42. Moreover, the proposed mechanisms of action, such as modulation of Akt, NF-κB pathway, and cell cycle-related proteins, were investigated by western blotting. (S)-HDAC42 exhibited four- to sevenfold higher potency relative to SAHA in suppressing myeloma cell viabilities. The apoptotic effect induced by (S)-HDAC42 was through both intrinsic and extrinsic pathways, as evidenced by increased cleavage of caspase-3, caspase-8, and caspase-9 and release of cytochrome c from mitochondria. In addition to HDAC inhibition, (S)-HDAC42 also disturbed signaling pathways governing cell survival, including downregulating Akt phosphorylation and NF-κB signaling. The modulation of cell cycle-related proteins by (S)-HDAC42 suggested its inhibitory effect on cell cycle propagation. These data suggest the translational value of (S)-HDAC42 in developing new therapeutic strategies for myeloma, which warrants further investigations.