Mitochondria: a target for cancer therapy

Abstract

Mitochondria, the cells powerhouses, are essential for maintaining cell life, and they also play a major role in regulating cell death, which occurs upon permeabilization of their membranes. Once mitochondrial membrane permeabilization (MMP) occurs, cells die either by apoptosis or necrosis. Key factors regulating MMP include calcium, the cellular redox status (including levels of reactive oxygen species) and the mobilization and targeting to mitochondria of Bcl-2 family members. Contemporary approaches to targeting mitochondria in cancer therapy use strategies that either modulate the action of Bcl-2 family members at the mitochondrial outer membrane or use specific agents that target the mitochondrial inner membrane and the mitochondrial permeability transition (PT) pore. The aim of this review is to describe the major mechanisms regulating MMP and to discuss, with examples, mitochondrial targeting strategies for potential use in cancer therapy.

Figure 1

Potential chemotherapeutic approaches targeting the mitochondrial outer membrane and the Bcl-2 family: mitochondrial outer membrane permeabilization is regulated by the Bcl-2 family of proteins therefore targeting strategies to induce apoptosis are aimed at either inhibiting Bcl-2 antiapoptotic proteins or inducing Bax-like proapoptotic proteins. (1) Use of gene silencing technology, for example, Genasense G3139 to downregulate Bcl-2 expression. (2) Bax vectors have been used to deliver Bax and form a pore in the MOM that releases proapoptotic cytochrome c and other factors from the intermembrane space. (3) BH3 stapled peptides (SAHBs) that activate Bax have been employed to induce apoptosis. (4) The caspases are negatively regulated by a family of proteins known as the IAPs including XIAP; however, these themselves are also regulated by the IAP-inhibitor proteins such as Smac/DIABLO, which serves to restore caspase activity. Smac/DIABLO mimics have recently been used to induce apoptosis (see text for references).

Figure 2

Potential chemotherapeutic approaches targeting the mitochondrial inner membrane and the mitochondrial permeability transition (PT). Mitochondrial inner membrane permeabilization and the PT is regulated by calcium and oxidative stress. Targeting strategies include activating the PT, inhibiting electron transport and oxidative phosphorylation and depleting mtDNA. (1) Agents such as arsenite, lonidamine, betulinic acid and CD437 target the PT and induce loss of Δψ_m. (2) Delocalized lipophilic cations accumulate in the mitochondria matrix due to the electrochemical gradient and cause loss of respiration and inhibition of electron transport. (3) α Helical peptides such as mastoparan and Vpr permeabilize mitochondrial membranes and induce PT. (4) Redox modulating compound such as diamide deplete GSH stores and oxidize and crosslink critical mitochondrial redox-sensitive thiol groups at the matrix surface of the PT. (5) mtDNA depleting agents such as ditercalinium inhibit respiration, electron transport and oxidative phosphorylation (see text for references).