PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells.

Abstract

Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels.

• Authors: Nilsa Rivera-Del Valle, Shan Gao, Claudia P Miller, Joy Fulbright, Carolina Gonzales, Mint Sirisawad, Susanne Steggerda, Jennifer Wheler, Sriram Balasubramanian, Joya Chandra
• Journal: International journal of cell biology (Int J Cell Biol) Vol. 2010 Pg. 207420 ( 2010) ISSN: 1687-8884 [Electronic] United States
• PMID: 20145726 (Publication Type: Journal Article)