Article

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

ABSTRACT 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.

2 Followers
 · 
157 Views
  • 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: Mitochondrial genome and functional alterations are related to various diseases including cancer. In all cases, the role of these organelles is associated with defects in oxidative energy metabolism and control of tumor-induced oxidative stress. The present study examines the involvement of mitochondrial DNA in cancer and in particular in breast cancer. Furthermore, since mitochondrial DNA is maternally inherited, hereditary breast cancer has been focused on.
    Current Genomics 05/2013; 14(3):195-203. DOI:10.2174/1389202911314030005 · 2.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidovanadium(IV) complexes [VO(py-aebmz)(B)]Cl (1, 2) and [VO(napth-py-aebmz)(cur)]Cl [3; py-aebmz = 2-(1H-benzimidazol-2-yl)-N-(pyridin-2-ylmethylene)ethanamine, HB = acetylacetone (Hacac, 1) and curcumin (Hcur, 2), napth-py-aebmz = naphthalimide conjugated to py-aebmz ] have been prepared, characterized and their photoinduced DNA cleavage activities and photocytotoxicities studied. Complexes 1–3 each exhibited an irreversible cyclic voltammetric response of the VIV/VIII redox couple at around –0.85 V versus SCE in dmf/0.1 M tbap. The complexes showed DNA photocleavage activity in visible light of 454, 530 and 647 nm through hydroxyl radical and singlet oxygen pathways. Fluorescence microscopy data suggest mitochondrial localization of complex 3 bearing a naphthalimide with a two-fold increase in photocytotoxicity in HaCaT cells with an IC50 value of 6.3 μM and a three-fold increase in MCF-7 cells with an IC50 of 5.4 μM compared with complex 2. Both 2 and 3 were non-toxic in the dark.
    European Journal of Inorganic Chemistry 05/2014; DOI:10.1002/ejic.201402001 · 2.97 Impact Factor
Show more

Preview

Download
2 Downloads
Available from