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The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest

Sesink, Anouk ; Becerra, Margaux ; Ruan, Jia Ling ; Leboucher, Sophie ; Dubail, Maxime ; Heinrich, Sophie ; Jdey, Wael ; Petersson, Kristoffer LU ; Fouillade, Charles and Berthault, Nathalie , et al. (2024) In NAR Cancer 6(1).
Abstract

AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This... (More)

AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
NAR Cancer
volume
6
issue
1
article number
zcae011
publisher
Oxford University Press
external identifiers
  • pmid:38476631
  • scopus:85187938797
ISSN
2632-8674
DOI
10.1093/narcan/zcae011
language
English
LU publication?
yes
id
85d4d61b-3020-466d-a9f2-df5c4d29b283
date added to LUP
2024-04-04 13:46:05
date last changed
2024-04-18 16:01:14
@article{85d4d61b-3020-466d-a9f2-df5c4d29b283,
  abstract     = {{<p>AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.</p>}},
  author       = {{Sesink, Anouk and Becerra, Margaux and Ruan, Jia Ling and Leboucher, Sophie and Dubail, Maxime and Heinrich, Sophie and Jdey, Wael and Petersson, Kristoffer and Fouillade, Charles and Berthault, Nathalie and Dutreix, Marie and Girard, Pierre Marie}},
  issn         = {{2632-8674}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{1}},
  publisher    = {{Oxford University Press}},
  series       = {{NAR Cancer}},
  title        = {{The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest}},
  url          = {{http://dx.doi.org/10.1093/narcan/zcae011}},
  doi          = {{10.1093/narcan/zcae011}},
  volume       = {{6}},
  year         = {{2024}},
}