TY - JOUR T1 - The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species JF - Proceedings of the National Academy of Sciences JO - Proc Natl Acad Sci USA SP - 10833 LP - 10838 DO - 10.1073/pnas.191208598 VL - 98 IS - 19 AU - Ruefli, Astrid A. AU - Ausserlechner, Michael J. AU - Bernhard, David AU - Sutton, Vivien R. AU - Tainton, Kellie M. AU - Kofler, Reinhard AU - Smyth, Mark J. AU - Johnstone, Ricky W. Y1 - 2001/09/11 UR - http://www.pnas.org/content/98/19/10833.abstract N2 - Many chemotherapeutic agents induce mitochondrial-membrane disruption to initiate apoptosis. However, the upstream events leading to drug-induced mitochondrial perturbation have remained poorly defined. We have used a variety of physiological and pharmacological inhibitors of distinct apoptotic pathways to analyze the manner by which suberoylanilide hydroxamic acid (SAHA), a chemotherapeutic agent and histone deacetylase inhibitor, induces cell death. We demonstrate that SAHA initiates cell death by inducing mitochondria-mediated death pathways characterized by cytochrome c release and the production of reactive oxygen species, and does not require the activation of key caspases such as caspase-8 or -3. We provide evidence that mitochondrial disruption is achieved by means of the cleavage of the BH3-only proapoptotic Bcl-2 family member Bid. SAHA-induced Bid cleavage was not blocked by caspase inhibitors or the overexpression of Bcl-2 but did require the transcriptional regulatory activity of SAHA. These data provide evidence of a mechanism of cell death mediated by transcriptional events that result in the cleavage of Bid, disruption of the mitochondrial membrane, and production of reactive oxygen species to induce cell death. GzB,granzyme B;SAHA,suberoylanilide hydroxamic acid;ROS,reactive oxygen species;P-gp,P-glycoprotein;HDAC,histone deacetylase;PARP,poly(ADP-ribose) polymerase;tBid,truncated Bid;Act D,actinomycin D;CHX,cycloheximide;STS,staurosporine;Vin,vincristine;CEM-CCRF,acute T cell leukemia cell line;ZFA-fmk and ZVAD-fmk,peptidyl fluoromethyl ketones;NAC,N-acetylcysteine;CCCP,carbonylcyanide m-chlorophenylhydrazone ER -