Abstract
The transformation of normal cells to the cancerous stage involves multiple genetic changes or mutations leading to hyperproliferation, resistance to apoptosis, and evasion of the host immune system. However, to accomplish hyperproliferation, cancer cells undergo profound metabolic reprogramming including oxidative glycolysis and acidification of the cytoplasm, leading to hyperpolarization of the mitochondrial membrane. The majority of drug development research in the past has focused on targeting DNA replication, repair, and tubulin polymerization to induce apoptosis in cancer cells. Unfortunately, these are not cancer-selective targets. Recently, researchers have started focusing on metabolic, mitochondrial, and oxidative stress vulnerabilities of cancer cells that can be exploited as selective targets for inducing cancer cell death. Indeed, the hyperpolarization of mitochondrial membranes in cancer cells can lead to selective importing of mitocans that can induce apoptotic effects. Herein, we will discuss recent mitochondrial-selective anticancer compounds (mitocans) that have shown selective toxicity against cancer cells. Increased oxidative stress has also been shown to be very effective in selectively inducing cell death in cancer cells. This oxidative stress could lead to mitochondrial dysfunction, which in turn will produce more reactive oxygen species (ROS). This creates a vicious cycle of mitochondrial dysfunction and ROS production, irreversibly leading to cell suicide. We will also explore the possibility of combining these compounds to sensitize cancer cells to the conventional anticancer agents. Mitocans in combination with selective oxidative-stress producing agents could be very effective anticancer treatments with minimal effect on healthy cells.
Highlights
Background of Mitochondria and CancerDespite many advances in cancer treatment approaches, cancer remains the leading cause of death in both Canada and the United States [1,2]
As a result of metabolic reprogramming by cancer cells, specific aspects of cancer cell metabolism may be distinct from normal healthy cells
We have demonstrated that a novel curcumin analogue, Compound A, showed high efficacy and induced selective apoptosis through the generation of reactive oxygen species (ROS) in a variety of cancer cell lines alone and in combination with another pro-oxidant, piperlongumine [120]
Summary
Despite many advances in cancer treatment approaches, cancer remains the leading cause of death in both Canada and the United States [1,2]. Cancer therapeutics including DNA damaging agents (e.g., cisplatin, doxorubicin, or 5-fluorouracil) and tubulin modifying agents (e.g., paclitaxel) have been developed to induce apoptosis in cancer cells These drugs have limitations due to their non-selective nature and extreme toxicity to healthy tissues. Aerobic glycolysis leads to the production of large amounts of lactate and pyruvate, causing increased acidity in the cytoplasm in cancer cells Their mitochondria are hyperpolarized compared with those of normal cells [27]. AIF-initiated apoptosis is caspase-independent, and works through chromatin condensation and DNA fragmentation [32] The presence of such pro-apoptotic proteins in the mitochondria puts a spotlight on the organelle as an interesting target for cancer therapy research. We will discuss some of the recent advances in the development of therapeutic modulators targeting mitochondrial vulnerabilities
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