PCI-24781, a novel hydroxamic acid HDAC inhibitor, exerts cytotoxicity and histone alterations via caspase-8 and FADD in leukemia cells

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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. © 2010 Nilsa Rivera-Del Valle et al.

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Chandra, J., Rivera-Del Valle, N., Gao, S., Miller, C. P., Fulbright, J., Gonzales, C., … Balasubramanian, S. (2010). PCI-24781, a novel hydroxamic acid HDAC inhibitor, exerts cytotoxicity and histone alterations via caspase-8 and FADD in leukemia cells. International Journal of Cell Biology. https://doi.org/10.1155/2010/207420

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