PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells.
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.
Department of Pediatrics Research, Children's Cancer Hospital, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Nilsa
N
Rivera-Del Valle
Shan
S
Gao
Claudia P
CP
Miller
Joy
J
Fulbright
Carolina
C
Gonzales
Mint
M
Sirisawad
Susanne
S
Steggerda
Jennifer
J
Wheler
Sriram
S
Balasubramanian
Joya
J
Chandra