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.
Highlights
The mitochondrion is probably the most studied eukaryotic cellular subcompartment due to its indispensable role in the regulation of cellular metabolism and multifaceted functions associated with various diseases, such as cancer, neurodegenerative diseases, and diabetes [1,2,3]
Lethal functions are mainly regulated by a process called mitochondrial outer membrane permeation (MOMP) [9], which occurs during an apoptotic trigger, mediated by the pore-forming activity of proapoptotic proteins, such as the Bcl-2 (B-Cell lymphoma 2) proteins, Bax (Bcl-2 associated X protein), and Bak (Bcl-2 antagonist/killer protein)
Since early introduced strategies for cancer targeting are described in detail in several reviews [1,4,5,17,18], in this review, we focus on recent strategies and progress in targeting mitochondria for cancer therapy
Summary
The mitochondrion is probably the most studied eukaryotic cellular subcompartment due to its indispensable role in the regulation of cellular metabolism and multifaceted functions associated with various diseases, such as cancer, neurodegenerative diseases, and diabetes [1,2,3]. 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]. Certain small cationic molecules, including rhodamine, pyridinium, and cyanine derivatives, have been shown to exhibit inherent mitochondria-penetrating ability [28,29] These compounds are extensively used as staining agents, mitochondrial fluorescent probes, imaging agents, and photodynamic therapy (PDT) agents as such or by conjugation with biologically relevant compounds (Figure 1). Several photosensitizers, such as metal complexes (Ir or Ru), IR 780, BODAPY, and indocyanine dyes, have been directed to the mitochondria and tested for tumor curing, showing improved results compared with analogs targeted to the cytoplasm or other organelles, especially under hypoxic condition
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