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bioRxiv · 10.1101/2025.04.07.647539

A novel antioxidant N-acetylcysteine Amide Alleviates Cyclophosphamide-induced Endothelial Damage

He, R.·Zheng, W.·Slof, T.·Wardell, E.·Mansson-Broberg, A.·Norgren, S.·Zhao, Y.·Hassan, M.
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Abstract

The alkylating agent cyclophosphamide (Cy) is one of the important corner stones in cancer treatment. Cy is used also as a part of conditioning regimens prior to hematopoietic cell transplantation and as a prophylactic treatment post transplantation in graft-versus-host disease. Existing evidence showed that high doses of Cy are associated with a number of side effects, including damage on arterial endothelium, which might contribute to late cardiovascular disorders. Oxidative stress has been characterized in such pathogenesis and is an exploitable target for treatment. Herein, the study aimed to investigate the protective role of the novel antioxidant N-acetylcysteine amide (NACA) in Cy-induced endothelial injury and explore the underlying mechanism. Our in vivo results showed that NACA partially reduced the endothelial injury and recovered the integrity of arterial endothelium in the mice treated with Cy. In addition, we found that NACA decreased the cytotoxicity of Cy on endothelial cells through alleviating caspase-dependent apoptosis, DNA damage and oxidative stress. Meanwhile, NACA pre-treatment rebalanced endothelial nitric oxide synthase (eNOS) and arginase I and preserved the angiogenic capability of endothelial cells which was compromised by Cy through blockage of Notch signaling pathway. Interestingly, in comparison to N-acetylcysteine (NAC), its amide derivative NACA showed superior ability to alleviate Cy-induced endothelial damage. In conclusion, the current study proved the robust endothelial protective potential of NACA, facilitating clinical use of the novel antioxidant.

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He, R., Zheng, W., Slof, T., Wardell, E., Mansson-Broberg, A., Norgren, S., Zhao, Y., Hassan, M.. 2025-04-11. A novel antioxidant N-acetylcysteine Amide Alleviates Cyclophosphamide-induced Endothelial Damage. https://doi.org/10.1101/2025.04.07.647539

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