4.6 Article

A linear five-ring pyrrole-imidazole polyamide-triphenylphosphonium conjugate targeting a mitochondrial DNA mutation efficiently induces apoptosis of HeLa cybrid cells carrying the mutation

Journal

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.08.088

Keywords

Pyrrole-imidazole polyamide; Triphenylphosphonium; Mitochondrial DNA mutation; mtROS; Mitophagy; Apoptosis

Funding

  1. Princess Takamatsu Cancer Research Fund
  2. JSPS KAKENHI [JP20H03540, JP26290060, JP17H03602, JP16H01579]
  3. AMED [18ae0101051, 21ek0109495s0201]
  4. Mother and Child Health Foundation [28-7]

Ask authors/readers for more resources

Somatic mutations in mitochondrial DNA present a potential avenue for cancer therapy, and short linear PI-TPPs demonstrate cytotoxic effects and induction of apoptosis in cells with A3243G mitochondrial mutations through targeted mitochondrial homing.
Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers anda 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 pre -serving 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. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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