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The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore.

2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its C(28) imidazole and dinitrile derivatives are novel oleanane triterpenoids exhibiting promise as both therapeutic and preventative agents for cancer. Herein we show that these triterpenoids induce normal and malignant B-lymphoid cell apoptosis, with the C(28) derivatives being more potent than CDDO, through a novel mitochondrial mechanism. We show using both normal and malignant human B cells, as well as isolated rat mitochondria, that CDDO directly interacts with a limited number of as yet undefined mitochondrial proteins. Such an interaction results in the loss of mitochondrial thiol status and the secondary modification of numerous mitochondrial protein thiols. Our data further suggest that such modifications result in the formation of high molecular weight protein aggregates that form "unregulated," constitutively open, cyclosporin A-insensitive permeability transition (PT) pores. The formation of such PT pores results in the subsequent generation of mitochondrial superoxide and cell death. In total, our studies (a) suggest a novel mechanism of action for triterpenoid-induced cell death; (b) are among the first to directly support the existence of an unregulated PT pore formed by mitochondrial protein aggregates, as first proposed by Lemasters and colleagues; and (c) validate such an unregulated PT pore as a viable target for the development of new cancer therapeutics.