Timohhina 2019 MiP2019

From Bioblast
Jump to: navigation, search
Natalja Timohhina
Metabolic effects of mitochondria-targeted antioxidant peptides in colorectal cancer cells.

Link: MiP2019

Timohhina N, Aid-Vanakova J, Chekulayev V, Kaambre T (2019)

Event: MiP2019

COST Action MitoEAGLE

Targeting the functional mitochondria in malignant cells is a promising approach in cancer therapy. Cell penetrating peptides provide such an opportunity to effectively cross inner membrane and deliver drug cargos without systemic side effects. Recently, Cerrato et al. synthesized the set of mitochondria-targeted peptides (mtCPPs) with the antioxidative effect in human primary glioblastoma, cervical carcinoma, and mouse brain epithelial cell lines [1, 2]. Here we investigate the mtCPPs antitumor effect and the influence on the bioenergetic parameters in human colon cancer-derived CaCo-2 intestinal epithelial cells.

A library of antioxidative mitochondrial and glutathione analogues were designed, synthesized, and kindly provided for our experiments by Prof. Ülo Langel research group (Stockholm University, Sweden). Four peptides were used in this study, mtCPP1, UPF25, mtgCPP, and mtCPPgOH. The cytotoxicity was evaluated by the widely used MTT assay. None of them at 5μM treatment showed any effect on human adenocarcinoma cells (CaCo2 cells). The same response was observed in HeLa cells, even at higher concentrations [1]. It was earlier reported that no change in mitochondrial membrane potential and ATP production after the mtCPPs access the mitochondria interior [1]. The studied cell line relies highly on glycolysis as an energy source. On the other hand, Caco-2 cells also display active mitochondrial oxidative phosphorylation function [3]. The mtCPPs influence on their bioenergetic profile was determined in the series of oxygraphic measurements. There were no statistically significant differences in the proton leak, ATP-linked respiration, maximal residual oxygen consumption, and reserve capacity between groups with peptides and the control. Functional activity of the pathways catalyzed by adenylate kinase and hexokinase and their OXPHOS coupling efficiency was also assessed. The corresponding indexes, the measured AMP- and glucose-mediated stimulation on maximal mitochondrial respiration, remained unaltered.

Despite the peptides antioxidant nature, the preliminary studies did not revealed any significant influence on the bioenergetics of the CaCo-2 cells. But there is still a possibility to use mtCPPs with conjugated potential drugs for precise intracellular cancer treatment.


Bioblast editor: Plangger M, Tindle-Solomon L O2k-Network Lab: EE Tallinn Kaambre T


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer 

Organism: Human  Tissue;cell: Endothelial;epithelial;mesothelial cell 


Coupling state: LEAK, OXPHOS, ET  Pathway: ROX  HRR: Oxygraph-2k 


Affiliations

Timohhina N(1), Aid-Vanakova J(1,2), Chekulayev V(1), Käämbre T(1)
  1. Lab Chemical Biology, NICPB
  2. Dep Chemistry Biotechnology, TUT, Tallinn, Estonia. - natalja.timohhina@kbfi.ee

References

  1. Cerrato CP, Kunnapuu K, Langel U (2017) Cell-penetrating peptides with intracellular organelle targeting. Expert Opin Drug Deliv 14:245-55.
  2. Cerrato CP, Pirisinu M, Vlachos EN, Langel U (2015) Novel cell-penetrating peptide targeting mitochondria. FASEB J 29:4589-99.
  3. Ounpuu L, Truu L, Shevchuk I, Chekulayev V, Klepinin A, Koit A, Tepp K, Puurand M, Rebane- Klemm E, Kaambre T (2018) Comparative analysis of the bioenergetics of human adenocarcinoma Caco-2 cell line and postoperative tissue samples from colorectal cancer patients. Biochem Cell Biol doi:10.1139/bcb-2018-0076.