Targeting mitochondria for cancer therapy.

Several recent insights into the roles of mitochondria in cancer have renewed efforts to develop nongenotoxic therapies targeting mitochondrial proteins and functions. Mitochondria are central hubs for intrinsic apoptotic pathways that are activated by cellular stress and injury, and as a consequence, cancers often have defects in these pathways. Bcl-2, the first identified regulator of apoptotic cell deaths, was discovered as an oncogene in human cancers. BCL-2 inhibits mitochondrial pathways of apoptosis through local effects at mitochondrial and endoplasmic reticulum membranes. Increased expression of BCL-2 and the related antiapoptotic proteins BCL-X(L), MCL-1, and BCL-W occurs in significant subsets of common cancer types (Table I) and is generally correlated with poor response. Although incomplete, the emerging understanding of BCL-2 functions through structural, biochemical, and organelle physiology studies has provided paths for targeting BCL-2 with small molecules. Cancer cells also exhibit metabolic differences with their normal cell counterparts, including aerobic glycolysis, known as the Warburg effect, mitochondrial membrane hyperpolarization, and unusual dependence on nutrient substrates such as glucose and glutamine. This knowledge has prompted reexamination of the potential cancer selectivity of previously identified mitochondriotoxic compounds, including approved drugs for other indications, and screening programs to identify new compounds with mitochondrial activities.