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Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9E 3P4, Canada
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Cancers 2019, 11(7), 916; https://doi.org/10.3390/cancers11070916
Received: 10 May 2019 / Revised: 19 June 2019 / Accepted: 25 June 2019 / Published: 29 June 2019
(This article belongs to the Special Issue Mitochondria and Cancer)
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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. View Full-Text
Keywords: mitochondria; apoptosis; oxidative phosphorylation; reactive oxygen species; metabolic reprogramming; electron transport chain; sensitization; chemoresistance mitochondria; apoptosis; oxidative phosphorylation; reactive oxygen species; metabolic reprogramming; electron transport chain; sensitization; chemoresistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Nguyen, C.; Pandey, S. Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells. Cancers 2019, 11, 916.

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