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

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.

• Authors: Nobuko Koshikawa, Yuki Kida, Nanami Yasui, Yoshinao Shinozaki, Kohei Tsuji, Takayoshi Watanabe, Jason Lin, Seigi Yamamoto, Keizo Takenaga, Hiroki Nagase
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 576 Pg. 93-99 (10 22 2021) ISSN: 1090-2104 [Electronic] United States
• PMID: 34482029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• DNA, Mitochondrial
• Imidazoles
• Nylons
• Organoselenium Compounds
• Pyrroles
• Reactive Oxygen Species
• triphenylselenonium chloride

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (physiology)
• DNA, Mitochondrial (drug effects, genetics)
• Female
• HeLa Cells
• Humans
• Imidazoles (chemistry)
• Mitophagy (physiology)
• Mutation
• Nylons (chemistry)
• Organoselenium Compounds (chemistry)
• Pyrroles (chemistry)
• Reactive Oxygen Species (metabolism)
• Uterine Cervical Neoplasms (drug therapy, genetics, metabolism)