Mitochondria as therapeutic targets for the treatment of malignant disease.

SIGNIFICANCE: Mitochondria exert vital functions during normal physiology and are also centrally involved in the regulation of various modes of cell death. Thus, engaging the mitochondrial apoptosis pathway presents an attractive possibility to activate lethal effectors in cancer cells. RECENT ADVANCES: Compounds that directly target mitochondria offer the advantage to initiate mitochondrial outer membrane permeabilization independently of upstream signal transduction elements that are frequently impaired in human cancers. As a consequence, mitochondrion-targeted agents may bypass some forms of drug resistance. CRITICAL ISSUES: An ever-increasing number of compounds, including natural compounds and rationally designed drugs, has been shown to directly act on mitochondria. FUTURE DIRECTIONS: Forthcoming insights into the fine regulation of mitochondrial apoptosis will likely open future perspectives for cancer drug development.