NMN Supplementation: A Shield Against Doxorubicin-Induced Multi-Organ Fibrosis
Introduction
In clinical settings, doxorubicin (DOX) is an effective broad-spectrum anti-cancer drug in chemotherapy for various tumors, including hematological malignancies and solid tumors such as leukemia, lymphoma, breast, ovarian and lung cancer. However, there is a formidable obstacle for the wide application of DOX, namely its toxic side effects on vital organs such as heart, liver and lung. Intriguingly, the toxic side effects of DOX are intricately linked to the involvement of nicotinamide adenine dinucleotide (NAD+). To this end, supplementing nicotinamide mononucleotide (NMN), an NAD+ precursor, may be an effective approach to mitigating the toxicity of DOX.About DOX
DOX, which is isolated from a soil bacterium, Streptomyces peucetius, was discovered in 1969 as a homolog of daunorubicin. Despite of its potent efficacy, long-term administration of DOX can cause severe damage to numerous organs in the body, with the heart being the primary target of doxorubicin toxicity. DOX has dose-dependent cardiotoxicity, including left ventricular dysfunction, progressive left ventricular remodeling and heart failure. Importantly, the accumulation of DOX can cause fibrosis which plays key roles in pathological development of multiple organs.
Multi-organ injury induced by DOX in mice
DOX leads to the toxicity to multiple organs, with the most prominent impacts upon heart, liver and lung. Morphologically, decreased thickness in the left ventricular posterior wall (LVPW), destroyed myocardium architecture, edema in hepatic cells and collapsed alveolar spaces are observed following DOX treatment. Besides, the reduced body weight (~20%) and organ weights, along with high mortality rate (60%), are viewed in post DOX injection. Moreover, NMN results in the reduced absolute number of hematopoietic stem/progenitor cells (HSPCs), short-term hematopoietic stem cells (ST-HSCs) and multipotent progenitors (MPPs).
The mitigating impacts of NMN upon DOX-induced toxicity
NMN supplementation attenuates DOX-induced toxicity to multiple organs and promotes the survival of mice by elevating NAD+ Level. Concretely, boosting NAD+ level through NMN supplementation alleviates the mitochondrial dysfunction, DNA damage and oxidation stress, as indicated by the elevated mitochondrial transmembrane potential (MTP) and ATP content as well as the reduced γH2AX and ROS levels. Additionally, NMN offsets the apoptosis of MRC5 fibroblasts, as supported by the downregulation of p21, an pro-apoptotic marker. Meanwhile, NMN supplementation alleviates the fibrosis of heart, liver and lungs, as evidenced by the reduced cellular damage and macrophage infiltration, as well as the downregulation of α-SMA, TGF-β1 and p-smad 2/3.
Conclusion
Upregulating NAD+ level via supplementation of NMN relieves cellular damage, fibrosis and macrophage infiltration caused by DOX, and improves the survival rate of mice, hinting its potential application prospect in mitigating the toxicity side effects of chemotherapeutic drug.
Reference
Wen F, Xu A, Wei W, et al. Nicotinamide Mononucleotide Supplementation Alleviates Doxorubicin-Induced Multi-Organ Fibrosis. Int J Mol Sci. 2024;25(10):5303. Published 2024 May 13. doi:10.3390/ijms25105303BONTAC NAD
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