Mitochondria as a Novel Target for Cancer Chemoprevention: Emergence of Mitochondrial-targeting Agents

Abstract

Cancer chemoprevention is the most effective approach to control cancer in the population. Despite significant progress, chemoprevention has not been widely adopted because agents that are safe tend to be less effective and those that are highly effective tend to be toxic. Thus, there is an urgent need to develop novel and effective chemopreventive agents, such as mitochondria-targeted agents, that can prevent cancer and prolong survival. Mitochondria, the central site for cellular energy production, have important functions in cell survival and death. Several studies have revealed a significant role for mitochondrial metabolism in promoting cancer development and progression, making mitochondria a promising new target for cancer prevention. Conjugating delocalized lipophilic cations, such as triphenylphosphonium cation (TPP+), to compounds of interest is an effective approach for mitochondrial targeting. The hyperpolarized tumor cell membrane and mitochondrial membrane potential allow for selective accumulation of TPP⁺ conjugates in tumor cell mitochondria versus those in normal cells. This could enhance direct killing of precancerous, dysplastic, and tumor cells while minimizing potential toxicities to normal cells.

Figure 1.. The basis for mitochondrial targeting using mito-compounds for cancer cell killing.

(A) Cancer cells have a more hyperpolarized membrane, which serves to drive the uptake of TPP⁺-conjugated compounds up to 100–1000-fold compared to extracellular compounds. Moreover, elevated ROS production in cancer cells renders them potentially more vulnerable to be killed by ROS-generating agents (like TPP⁺-conjugated compounds). (B) Normal cells have a less hyperpolarized mitochondrial membrane and comparatively lower levels of ROS, which leads to less uptake of mito-compounds and insufficient ROS to initiate cell death.

Figure 2.

Chemical structures of representative mitochondria-targeted compounds.

Figure 3.. Potential anticancer activities of mitochondria-targeted compounds (MTC).

Inhibition on ETC by MTC (A) leads to mitochondrial uncoupling, with overproduction of mitochondrial ROS (B) (31, 32), and decreases in ATP generation (C) (30, 109). The initial production of mitochondrial ROS can lead to membrane potential dissipation (D) (69, 96, 115), and opening of the mitochondrial permeability transition pore (mPTPC) (E) (73). The opening of the mPTPC could intensify mitochondrial ROS production (F) (191), allowing large amounts of solutes to enter the mitochondrial matrix and cause necrosis-like cell death (G) (191), and release of cytochrome c (Cyt C) into cytosol to trigger apoptosis (H) (73, 115, 156). Induction of mitochondrial outer membrane permeabilization (MOMP, I) (152), inhibition of Kv1.3 channels (J) (155) and TrxR activity (K) (69) by MTC could also promote more ROS production. Excessive mitochondrial ROS can damage mitochondrial DNA (L) (118) and telomeric nuclear DNA (nDNA) (M) (192). These mitochondrial stressors can potentially lead to autophagy-induced cell death (N) (32).