An antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage

Jae Kyung Nam, A. Ram Kim, Seo Hyun Choi, Ji Hee Kim, Kyu Jin Choi, Seulki Cho, Jae Won Lee, Hyun Jai Cho, Yoo Wook Kwon, Jaeho Cho, Kwang Seok Kim, Joon Kim, Hae June Lee, Tae Sup Lee, Sangwoo Bae, Hyo Jeong Hong, Yoon Jin Lee

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial–mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart–irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.

Original languageEnglish
Article number3279
JournalNature communications
Issue number1
Publication statusPublished - 2021 Dec 1

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation (NRF-2017M2A2A7A02019482, NRF-2020M2D9A2093964, NRF-2020M2C8A2069337, NRF-2018R1D1A1A09084274 and NRF-2020R1A2B5B02002709) and the Korea Institute of Radiological & Medical Sciences (KIRAMS, 50531-2021) funded by the Ministry of Science and ICT (MSIT), Republic of Korea.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General
  • General Physics and Astronomy


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