Arsenic Trioxide, a Novel Mitochondriotoxic Anticancer Agent?

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Abstract
During the last few years, it has become increasingly clear that mitochondria play a major rate-limiting role in apoptosis ( 1 - 3 ). In general terms, the apoptotic process can be subdivided into three phases: the initiation phase, the decision/effector phase, and the degradation phase. During the heterogeneous initiation phase, which is essentially premitochondrial, specific pro-apoptotic signal transduction pathways or nonspecific damage pathways are activated. These pathways converge on the mitochondria during the decision/effector phase, where they trigger progressive permeabilization of mitochondrial membranes, mostly as a result of the action of the permeability transition pore complex (PTPC). Thus, the mitochondrion (or to be more precise, the PTPC, which interacts with the Bcl-2/Bax complex) “decides” the cell's fate and determines the point of no return of the process ( 4 , 5 ). The morphologic and biochemical features of apoptosis become manifest during the postmitochondrial degradation phase, in which soluble intermembrane proteins (SIMPs) released from mitochondria play an active role: AIF (apoptosis-inducing factor) translocates to the nucleus, where it induces large-scale DNA fragmentation ( 6 ); cytochrome c triggers the activation of pro-caspase-9 ( 7 ); and pro-caspases 2, 3, and 9 intervene in a cascade of proteolytic destruction ( 8 , 9 ). Inhibition of SIMPs does not prevent cell death as such, although it may cause a shift from apoptotic to non-apoptotic cell death ( 2 ).