We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Antitumor effects of ( S)-HDAC42, a phenylbutyrate-derived histone deacetylase inhibitor, in multiple myeloma cells.
- Authors
Bai, Li-Yuan; Omar, Hany; Chiu, Chang-Fang; Chi, Zeng-Pang; Hu, Jing-Lan; Weng, Jing-Ru
- 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.
- Subjects
ANTINEOPLASTIC agents; HISTONE deacetylase; ENZYME inhibitors; DRUG efficacy; FLOW cytometry; APOPTOSIS; PROTEIN kinases; PHOSPHORYLATION
- Publication
Cancer Chemotherapy & Pharmacology, 2011, Vol 68, Issue 2, p489
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-010-1501-z