Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

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.

Malva pseudolavatera Leaf Extract Promotes ROS Induction Leading to Apoptosis in Acute Myeloid Leukemia Cells In Vitro

“…This promotes the release of cytochrome-c from the mitochondria, explaining its upregulation, which is essential for the activation of caspases leading to apoptosis [37]. In fact, exploiting chemotherapeutic effects on mitochondrial membrane leakage was shown to be effective in selectively triggering apoptosis in cancer cells since metabolic reprogramming is an inherent step required for hyperproliferation of cancer cells [38].…”

Induction of Apoptosis by Coptisine in Hep3B Hepatocellular Carcinoma Cells through Activation of the ROS-Mediated JNK Signaling Pathway

“…On the one hand, in the extrinsic pathway, apoptosis is induced by external signals, which directly activate caspase-8, and activated caspase-8 induces the activation of executioner caspases including caspase-3 and caspase-7 [35,36]. On the other hand, activation of the intrinsic pathway is associated with impaired mitochondrial function, regulated by internal signals, and linked to changes in the expression of Bcl-2 family proteins [35,37]. When the expression of proapoptotic members belonging to the Bcl-2 family proteins was increased as compared with the expression of anti-apoptotic members, mitochondrial permeability increased, and proapoptotic proteins, such as cytochrome c, were released into the cytoplasm.…”

Involvement of Mitochondrial Mechanisms in the Cytostatic Effect of Desethylamiodarone in B16F10 Melanoma Cells

“…However, resistance to apoptosis is a hallmark of cancer that is achieved by disrupting the balance between pro- and anti-apoptotic Bcl2 proteins [ 66 ]. Resistance arises due to a multitude of mechanisms, including the downregulation of pro-apoptotic, up-regulation of anti-apoptotic Bcl-2 genes [ 67 ], and upregulation of protein inhibitors of apoptosis [ 68 ]. Although only preliminary data are available regarding how DEA interferes with these mechanisms, some trends have emerged.…”