Small mitochondria-targeting molecules as anti-cancer agents

Abstract

Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anti-cancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed.

Figure 1

Overview of possible sites and functions of mitochondria as potential targets for anticancer therapy. (1) Certain compound, often with positive charge, may preferentially accumulate in the mitochondria of cancer cells due to the elevated transmembrane potential (Δψm), with the inner surface of the inner mitochondrial membrane being highly negatively-charged. (2) Mitochondrial DNA, which encodes 13 key components of the respiratory chain complexes, are vulnerable to damage by certain DNA-interacting compounds due to the unique structure of mitochondrial DNA, lack of histone protection, and relatively weak DNA repair capacity in the mitochondria. (3) Inhibition of mitochondrial respiration through targeting the electron transport complexes has been shown to elevate ROS production, deplete ATP and induce apoptosis. (4) Targeting the mitochondriapermeability transition pore (MPTP) may alter Δψm, induce change in membrane permeability, and result in a release of apoptotic factors. (5) Enzymes of the glycolytic pathways are often found elevated in cancer cells with mitochondrial dysfunction, likely being a mechanism to compensate energy supply and provide metabolic intermediates for cell growth and proliferation. Inhibition of glycolytic enzymes has been shown to preferentially kill cancer cells, especially those with significant mitochondrial dysfunction or under hypoxic conditions. 3BrPA, 3-bromopyruvate; HXK, hexokinase; LDH, lactate dehydrogenase; PDH, pyruvade dehydrogenase; PDK, pyruvate dehydrogenase kinase; Δψm, mitochondria transmembrane potential; mtDNA, mitochondrial DNA (Δψm). MPTP, mitochondrial permeability transition pore.