NAD+ administration decreases doxorubicin-induced liver damage of mice by enhancing antioxidation capacity and decreasing DNA damage
Graphical abstract
Introduction
Cancer is one of the leading causes of death in the world. One of the major obstacles for establishing effective therapeutic strategies for cancer is the toxic side effects of most anti-cancer drugs [8], [16], [24], [26], which can damage such organs and systems as the immune system, liver and heart [13], [14]. Thus, it is of crucial importance to find effective approaches to decrease the toxic side effects of anti-cancer drugs. Doxorubicin (DOX) is one of the most widely used anti-cancer drugs. The action mechanisms of DOX include: DOX interacts with DNA by intercalation and inhibition of macromolecular biosynthesis, which inhibits the progression of the enzyme topoisomerase II, thus blocking the process of replication [10], [18]. The therapeutic efficacy of DOX have been severely limited by the toxic side effects of the drug on heart as well as other organs including the liver, brain and kidney [8], [26]. Multiple studies have reported that DOX can impair cardiomyocytes by generating oxidative stress [9]. It has also been reported that such antioxidants as Vitamin E and N-acetyl-cysteine (NAC) can decrease DOX-induced liver damage [7], [11], [15]. It is of great significance to find new approaches that can decrease DOX-induced liver damage, so as to enhance the beneficial effects of DOX.
NAD+ is a fundamental molecule in cells, which plays important roles in energy metabolism, mitochondrial functions and calcium homeostasis [31]. Previous studies by our laboratory and other laboratories have shown that NAD+ treatment can decrease oxidative stress-induced cell death in vitro [1], [2], and NAD+ administration can also reduce both ischemic and traumatic brain damage in vivo [29], [32]. However, it remains unknown if NAD+ treatment may directly increase antioxidation capacity of cells or tissues. In current study, we used a mouse model to test our hypotheses that NAD+ administration may decrease DOX-induced liver damage, and that NAD+ administration can enhance the antioxidation capacity of the DOX-exposed liver. Our results have provided evidence supporting these hypotheses.
Section snippets
Materials
The chemicals and antibodies used in this study were purchased from Sigma Chemicals (St. Louis, MO, USA) except where noted.
Procedures of animal operation
Male ICR mice weighing 20–25 g were purchased from SLRC Laboratory (Shanghai, China). All of the animal protocols were approved by the Animal Study Committee of the School of Biomedical Engineering, Shanghai Jiao Tong University. To induce acute hepatic injury, mice were injected intraperitoneally with 20 mg/kg doxorubicin hydrochloride (DOX) dissolved in saline. For a
Effects of NAD+ administration on DOX-induced increases in SGOT activity and decreases in liver weight and body weight
We determined the effect of NAD+ administration on DOX-induced hepatotoxicity of mice by measuring the activity of the hepatic function-associated enzyme in the serum, as well as the liver weight and the body weight (Fig. 1). We found that DOX induced a significant increase in the activity of SGOT activity, which was significantly attenuated by the NAD+ administration (Fig. 1A). We also found that DOX administration led to significant decreases in both the liver weight (Fig. 1B) and body weight
Discussion
The major findings of this study include: First, NAD+ administration can significantly attenuate DOX-induced increases in the markers of liver injury; second, NAD+ administration can attenuate DOX-induced apoptotic changes, including increased caspase-3 activity and increased TUNEL signals; third, NAD+ administration can reduce DOX-induced dsDNA damage; and fourth, NAD+ administration can prevent DOX-induced decreases in the GSH levels in the liver, which could at least partially account for
Conflict of interest
There is no any competing interests.
Acknowledgment
This study was supported by a National Key Basic Research ‘973 Program’ Grant #2010CB834306 (to W.Y.), the Natural Science Foundation of Shanghai, China (Grant #12ZR1428800), Chinese National Science Foundation Grants #81171098 and #81271305 (to W.Y.) and #81302004 (to T.C.), and Shanghai Jiao Tong University Grant for Interdisciplinary Research on Medicine and Engineering (to W.Y. and T.C.).
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These authors contributed equally.