Chemotherapy: targeting the mitochondrial cell death pathway

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Abstract
One of the mechanisms by which chemotherapeutics destroy cancer cells is by inducing apoptosis. Apoptosis can be activated through several different signalling pathways, but these all appear to converge at a single event – mitochondrial membrane permeabilization (MMP). This ‘point-of-no-return’ in the cell death program is a complex process that is regulated by the composition of the mitochondrial membrane and pre-mitochondrial signal-transduction events. MMP is subject to a complex regulation, and local alterations in the composition of mitochondrial membranes, as well as alterations in pre-mitochondrial signal-transducing events, can determine chemotherapy resistance in cancer cells. Detecting MMP might thus be useful for detecting chemotherapy responses in vivo. Several cytotoxic drugs induce MMP by a direct action on mitochondria. This type of agents can enforce death in cells in which upstream signals normally leading to apoptosis have been disabled. Cytotoxic components acting on mitochondria can specifically target proteins from the Bcl-2 family, the peripheral benzodiazepin receptor, or the adenine nucleotide translocase, and/or act by virtue of their physicochemical properties as steroid analogues, cationic ampholytes, redox-active compounds or photosensitizers. Some compounds acting on mitochondria can overcome the cytoprotective effect of Bcl-2-like proteins. Several agents which are already used in anti-cancer chemotherapy can induce MMP, and new drugs specifically designed to target mitochondria are being developed.