Li-Yuan Bai, Hany A. Omar, Chang-Fang Chiu, Zeng-Pang Chi, Jing-Ru Weng. Antitumor effects of (S)-HDAC42, a phenylbutyrate-derived histone deacetylase inhibitor, in multiple myeloma cells. Cancer Chemotherapy and Pharmacology, 2010 Aug;68(2):489-96

Research Abstract

Purpose 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. Methods 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. Results (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. Conclusion These data suggest the translational value of (S)-HDAC42 in developing new therapeutic strategies for myeloma, which warrants further investigations.

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