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A linear five-ring pyrrole-imidazole polyamide-triphenylphosphonium conjugate targeting a mitochondrial DNA mutation efficiently induces apoptosis of HeLa cybrid cells carrying the mutation.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2021 Oct 22; Vol. 576, pp. 93-99. Date of Electronic Publication: 2021 Aug 31. - Publication Year :
- 2021
-
Abstract
- Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers and a tendency of homoplasmicity. In consideration of mitochondrial features and its relatively small genome size, a nucleotide-based targeting approach is a considerably more promising option. To explore the efficacy of short linear N-methylpyrrole-N-methylimidazole polyamide (PI polyamide), we synthesized a five-ring short PI polyamide that provided sequence-specific homing for the A3243G mitochondrial mutation upon conjugation with triphenylphosphonium cation (TPP). This PI polyamide-TPP was able to induce cytotoxicity in HeLamtA3243G cybrid cells, while preserving preferential binding for oligonucleotides containing the A3243G motif from melting temperature assays. The PI polyamide-TPP also localized in the mitochondria in HeLamtA3243G cells and induced mitochondrial reactive oxygen species production, mitophagy and apoptosis in a mutation-specific fashion compared to the wild-type HeLamtHeLa cybrids; normal human dermal fibroblasts were also relatively unaffected to suggest discriminating selectivity for the mutant mitochondria, offering a novel outlook for cancer therapy via mitochondrial homing of short linear PIP-TPPs.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemistry
Apoptosis physiology
DNA, Mitochondrial genetics
Female
HeLa Cells
Humans
Mitophagy physiology
Reactive Oxygen Species metabolism
Uterine Cervical Neoplasms genetics
Uterine Cervical Neoplasms metabolism
Antineoplastic Agents pharmacology
DNA, Mitochondrial drug effects
Imidazoles chemistry
Mutation
Nylons chemistry
Organoselenium Compounds chemistry
Pyrroles chemistry
Uterine Cervical Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 576
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 34482029
- Full Text :
- https://doi.org/10.1016/j.bbrc.2021.08.088