MITOCHONDRIA IN CHEMOTHERAPY-INDUCED APOPTOSIS - A PROSPECTIVE NOVEL TARGET OF CANCER-THERAPY (REVIEW)

Resistance to apoptosis is a frequent characteristic of cancer cells a nd participates both in the initial phase of carcinogenesis and in the development of chemotherapy resistance. Recently, it has become clear that a disruption in mitochondrial membrane function is a decisive ev ent of the apoptotic process leading to the disposal of chemotherapy-t reated cells. Opening of the mitochondrial megachannel (also called pe rmeability transition pore) is at least in part responsible for the di sruption of mitochondrial membrane integrity in apoptosis. The megacha nnel is regulated by numerous endogenous effecters including members o f the Bcl-2/Bax family, the redox status of the cell, cytosolic Ca2+ l evels, ceramide, and amphipathic peptides. Chemotherapeutic agents may induce opening of the megachannel by modulating some of these endogen ous effecters. The disruption of mitochondrial membrane integrity invo lves a loss of metabolic functions and the liberation of intermembrane proteins into the cytosol. Such proteins, which normally are well sec luded in mitochondria, include cytochrome c and AIF (apoptosis inducin g factor), which both activate caspases and endonucleases upon release into the cytosol. Strategies for the development of chemotherapeutic agents acting on mitochondria are discussed.