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

Abstract

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.

L1 cell adhesion molecule may be a protective molecule for atrial fibrillation in patients with valvular heart disease

“…Numerous studies have discovered that different localized L1CAMs exerted different functions by mediating different mechanisms, and participated in various disease processes. Nam JK et al showed that fibrotic phenotype (endothelial–mesenchymal transition, EndMT) may be seen in vascular endothelial cells when persistent DNA damage has been caused by irradiation and subsequent treatment with Dox correlating with the colocalization of L1CAM and persistent DNA damage foci [ 18 ]. Moreover, the use of the anti-L1CAM antibody in therapy has the potential to attenuate L1CAM overexpression as well as nuclear translocation and persistent DNA damage foci [ 18 ].…”

“…However, the investigation of the function of L1CAM in AF, as well as other cardiac disease, was extremely rare. By modulating the extent of persistent DNA damage, an antibody that targets the L1 cell adhesion molecule may suppress cardiotoxicity [ 18 ]. L1CAM was an essential component in the cell adhesion process, working in conjunction with neural cell adhesion molecule (NCAM).…”

The Impairment of Cell Metabolism by Cardiovascular Toxicity of Doxorubicin Is Reversed by Bergamot Polyphenolic Fraction Treatment in Endothelial Cells

“…DOX is the most widely used anthracycline in numerous neoplastic diseases, despite the fact that its cardiotoxicity is an important side effect [ 5 , 6 ]. In fact, in addition to causing acute toxicity that is reversible, DOX, over the years, can generate a progressive injury process, causing a dose-dependent risk of heart failure [ 5 , 6 , 7 ]. At the level of tumor cells, DOX inhibits proliferation and leads to cell death as it intercalates with DNA in the nucleus and inhibits topoisomerase IIα (Top IIα) [ 5 ].…”

Synthesis of bimetal MOFs for rapid removal of doxorubicin in water by advanced oxidation method

“…1 Among them, doxorubicin hydrochloride (DOX) is the most common anti-cancer drug that has frequently been reported to have been detected in sewage systems. 2,3 With the widespread use of DOX in tumor treatment, DOX enters groundwater and penetrates into the soil, causing DOX to accumulate easily in plants and eventually to enter the human body through the food chain. 4 Unfortunately, when DOX is accumulated to a certain extent, it will cause the body's immune system to decline and cause pollution to the natural environment.…”