Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

Abstract

The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches.In healthy cells, mitochondria execute a controlled regulation of multiple functions to maintain the cellular growth-death cycle. However, in the case of tumor cells, to meet the higher metabolic demand of rapidly proliferating cells, dysregulation of mitochondrial metabolism occurs [14,15]. The difference between cancer cell mitochondria and normal cells includes several functional alterations, such as mutation of mtDNA that lead to OXPHOS (oxidative phosphorylation) inhibition and thus deficient respiration and ATP generation, mutation of mtDNA-encoded mitochondrial enzymes, such as SDH (succinate dehydrogenase), IDH1 (isocitrate dehydrogenase 1), IDH2 (isocitrate dehydrogenase 2) [16], and structural differences, such as higher membrane potential of cancer cell mitochondria and higher basicity inside the mitochondrial lumen. The evasion of cell death or inhibition of mitochondria-mediated apoptosis is a hallmark for cancer. Mitochondria generate ROS, which is necessary for signaling under normal conditions. However, when apoptosis is inhibited in the case of cancer, ROS contributes to the neoplastic transformation. Furthermore, for supporting tumor cell survival under harsh tumorigenic conditions, such as nutrient depletion and hypoxia, mitochondria provide flexibility in several pathways either by up-or downregulation [17]. This altered mitochondrial metabolism of cancer cells compared with that of their normal counterparts is advantageous for the selective targeting of cancer mitochondria in therapeutics, which focuses on the cancer mitochondria specific features [18]. Directing the therapeutic agent to the mitochondria is an efficient way of eliminating cancer cells because the designed drug molecules could act at the central point of the cell, and therefore, engineering mitochondrial-targeted therapeutic agents have gained much interest in cancer thera...

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