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

Many chemotherapeutic agents induce mitochondrial-mem bra ne disruption to initiate apoptosis. However, the upstream events leading to drug-induced mi tochondrial perturbation have remained poorly defined. We have used a varie ty of physiological and pharmacological inhibitors of distinct apoptotic pa thways 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 mitochond ria-mediated death pathways characterized by cytochrome c release and the p roduction of reactive oxygen species, and does not require the activation o f key caspases such as caspase-8 or -3. We provide evidence that mitochondr ial disruption is achieved by means of the cleavage of the BH3-only proapop totic 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 tran scriptional regulatory activity of SAHA. These data provide evidence of a m echanism of cell death mediated by transcriptional events that result in th e cleavage of Bid, disruption of the mitochondrial membrane, and production of reactive oxygen species to induce cell death.