PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells. (6th December 2009)

• Record Type: Journal Article
• Authors: Rivera-Del Valle, Nilsa; Gao, Shan; Miller, Claudia P.; Fulbright, Joy; Gonzales, Carolina; Sirisawad, Mint; Steggerda, Susanne; Wheler, Jennifer; Balasubramanian, Sriram; Chandra, Joya
• Other Names: Fulda Simone Academic Editor.
• Is Part Of: International journal of cell biology. Volume 2010(2010)
• Publication Date: 2009-12-06
• Subjects: Cytology -- Periodicals; Cell Biology; Cytology; Periodicals; Electronic journals -- Sciences; Electronic journals -- Biology; Periodicals; 571.6
• DOI: 10.1155/2010/207420
• Languages: English
• ISSNs: 1687-8876

Abstract

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.