NAD+ administration decreases doxorubicin-induced liver damage of mice by enhancing antioxidation capacity and decreasing DNA damage

Abstract

One of the major obstacles for cancer treatment is the toxic side effects of anti-cancer drugs. Doxorubicin (DOX) is one of the most widely used anti-cancer drugs, which produces significant toxic side effects on the heart and such organs as the liver. Because NAD+ can decrease cellular or tissue damage under multiple conditions, we hypothesized that NAD+ administration may decrease DOX-induced hepatotoxicity. In this study we tested this hypothesis by using a mouse model, showing that NAD+ administration can significantly attenuate DOX-induced increase in serum glutamate oxaloacetate transaminase activity and decrease in liver weight. The NAD+ administration also attenuated the DOX-induced increases in the levels of double-strand DNA (dsDNA) damage, TUNEL signals, and active caspase-3. Furthermore, our data has suggested that the NAD+ administration could produce protective effects at least partially by restoring the antioxidation capacity of the liver, because NAD+ administration can attenuate the decreases in both the GSH levels and the glutathione reductase activity of the DOX-treated liver, which could play a significant role in the DOX-induced hepatotoxicity. This finding has provided the first evidence indicating that NAD+ is capable of increasing the antioxidation capacity of tissues. Collectively, our study has found that NAD+ can significantly decrease DOX-induced liver damage at least partially by enhancing antioxidation capacity and decreasing dsDNA damage. Because it can also selectively decrease tumor cell survival, NAD+ may have significant merits over antioxidants for applying jointly with DOX to decrease the toxic side effects of DOX.