Targeting malignant mitochondria with therapeutic peptides

Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84108, USA.
Therapeutic delivery 08/2012; 3(8):961-79. DOI: 10.4155/tde.12.75
Source: PubMed


The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondira often rely on disruption of protein--protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion.

19 Reads
  • Source
    • "Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria [16]. Therefore, we detected whether the mitochondrial pathway was involved in EMAP II inducing apoptosis of C6 glioma cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study was performed to examine whether Endothelial-monocyte-activating polypeptide II (EMAP II) could inhibit glioma growth by inducing rat brain glioma C6 cells apoptosis. The results revealed that the EMAP II decreased cell viability of rat C6 glioma cells in a time-dependent manner. Apoptotic proportion was increased gradually after EMAP II. EMAP II induced the decrease in mitochondrial membrane potential and the release of cytochrome c into the cytosol, followed by activation of caspase-9 and caspase-3. Meanwhile, EMAP II-induced apoptosis was accompanied by an increase of reactive oxygen species (ROS). The significant up-regulation in the expressions of Bax and Apaf-1 as well as down-regulation in the expression of Bcl-2 was observed. The time course change of ROS was prior to the changes of above investigated indexes. All of these results strongly suggest that EMAP II could induce rat C6 glioma cells apoptosis via the mitochondrial pathway, and ROS, Bax/Bcl-2 might be involved in this processing. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 01/2015; 457(4). DOI:10.1016/j.bbrc.2015.01.030 · 2.30 Impact Factor
  • Source
    • "One of the key differences between malignant and healthy mitochondria may be the high mitochondrial membrane potential (Δψm) [21]. Even slight gains in Δψm have been proposed to confer to cationic agents a greater targeting of mitochondrial membranes and, consequently, better membrane permeabilization and cell death induction in cancer cells [22]. To further provide insight into the interaction of KLA with mitochondrial membrane lipids, a biophysical approach has been chosen (3.3 below). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The peptide KLA (acetyl-(KLAKLAK)2-NH2), which is rather non toxic for eukaryotic cell lines, becomes active when coupled to the cell penetrating peptide, penetratin (Pen), by a disulfide bridge. Remarkably, the conjugate KLA-Pen is cytotoxic, at low micromolar concentrations, against a panel of seven human tumor cell lines of various tissue origins, including cells resistant to conventional chemotherapy agents but not to normal human cell lines. Live microscopy on cells possessing fluorescent labeled mitochondria shows that in tumor cells, KLA-Pen had a strong impact on mitochondria tubular organization instantly resulting in their aggregation, while the unconjugated KLA and pen peptides had no effect. But, mitochondria in various normal cells were not affected by KLA-Pen. The interaction with membrane models of KLA-Pen, KLA and penetratin were studied using dynamic light scattering, calorimetry, plasmon resonance, circular dichroism and ATR-FTIR to unveil the mode of action of the conjugate. To understand the selectivity of the conjugate towards tumor cell lines and its action on mitochondria, lipid model systems composed of zwitterionic lipids were used as mimics of normal cell membranes and anionic lipids as mimics of tumor cell and mitochondria membrane. A very distinct mode of interaction with the two model systems was observed. KLA-Pen may exert its deleterious and selective action on cancer cells by the formation of pores with an oblique membrane orientation and establishment of important hydrophobic interactions. These results suggest that KLA-Pen could be a lead compound for the design of cancer therapeutics.
    Biochimica et Biophysica Acta 05/2014; 1838(8). DOI:10.1016/j.bbamem.2014.04.025 · 4.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ataxia telangiectasia (AT) is a pleiotropic genetic disorder characterized by progressive neurodegeneration, especially of cerebellar Purkinje cells, immunodeficiency, increased incidence of cancer, and premature aging. The disease is caused by functional inactivation of the ATM (AT-mutated) gene product, which is thought to act as a sensor of reactive oxygen species and oxidative damage of cellular macromolecules and DNA. The compound phenotype of AT might thus be linked to a continuous state of oxidative stress leading to an increase of programmed cell death (apoptosis). To assess this hypothesis, we analyzed lipid peroxidation products and the oxidative stress associated DNA base damage 8-hydroxy-2-deoxyguanosine in patients with AT. Oxidative damage to lipids and DNA was found to be markedly increased in AT patients. These results indicate that ATM might play an important role in the maintenance of cell homeostasis in response to oxidative damage. In this context, a better control of levels of reactive oxygen species could be a rational foundation of therapeutic intervention to help alleviate some of the symptoms associated with AT.
    Antioxidants and Redox Signaling 07/2002; 4(3):465-9. DOI:10.1089/15230860260196254 · 7.41 Impact Factor
Show more

Preview (2 Sources)

19 Reads
Available from