Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore

The molecular mode of action of arsenic, a therapeutic agent employed in th e treatment of acute promyelocytic leukemia, has been elusive, Here we prov ide evidence that arsenic compounds may act on mitochondria to induce apopt osis, Arsenite induces apoptosis accompanied by a loss of the mitochondrial transmembrane potential (Delta psi(m),). Inhibition of caspases prevents t he arsenite-induced nuclear DNA loss, but has no effect on the Delta psi(m) , dissipation and cytolysis induced by arsenite. In contrast, Bcl-2 express ion induced by gene transfer prevents all hallmarks of arsenite-induced cel l death, including the Delta psi(m) collapse, PK11195, a ligand of the mito chondrial benzodiazepine receptor, neutralizes this Bcl-2 effect. Mitochond ria are required in a cell-free system to mediate arsenite-induced nuclear apoptosis. Arsenite causes the release of an apoptosis-inducing factor (ATF ) from the mitochondrial intermembrane space. This effect is prevented by t he permeability transition (PT) pore inhibitor cyclosporin A, as well as by Bcl-2, which is known to function as an endogenous PT pore antagonist. Ars enite also opens the purified, reconstituted PT pore in vitro in a cyclospo rin A- and Bcl-2-inhibitible fashion. Altogether these data suggest that ar senite can induce apoptosis via a direct effect on the mitochondrial PT por e, (C) 1999 Academic Press.