Targeting mitochondria for cancer therapy

Mitochondria exert both vital and lethal functions in physiological and pathological conditions. Mitochondria are not only indispensable for energy production and the survival of eukaryotic cells, but are also crucial regulators of the intrinsic (mitochondrial) pathway of apoptosis.Mitochondrial functions are frequently altered in cancers. Most classical anticancer agents engage signalling pathways that lie upstream of mitochondria and converge on these organelles to trigger cell death. Thus, drugs that directly target mitochondria constitute unique tools to bypass drug resistance.Metabolic reprogramming is a central feature of cancer cells that is intricately linked to mitochondria and provides unique opportunities for the development of drugs that target the Achilles' heel of cancer.The permeabilization of mitochondrial membranes constitutes a central event during mitochondrial apoptosis. Several classes of pharmacological compounds have been identified that impinge on mitochondrial membrane permeabilization, including modulators of the B-cell lymphoma protein 2 (BCL-2) protein family, metabolic inhibitors, voltage-dependent anion channel (VDAC)-targeting and adenine nucleotide translocase (ANT)-targeting agents, redox-active molecules, retinoids, heat-shock protein 90 (HSP90) inhibitors, as well as natural compounds with distinct mechanisms of action.Several mitochondrially-targeted agents with anticancer activity are derived from natural compounds and have been identified by serendipity rather than by high-throughput screening methods. Thus, the systematic screening of large libraries of natural substances most likely represents a treasure trove for anticancer drug discovery.Mitochondria are the most prominent source of intracellular reactive oxygen species (ROS) and low levels of ROS have been implicated in cancer cell stemness. Mitochondrially-targeted redox-active agents may therefore provide a novel strategy to selectively target cancer stem cells.