NAD(+) Administration Decreases Doxorubicin-Induced Liver Damage of Mice by Enhancing Antioxidation Capacity and Decreasing DNA Damage

Chem Biol Interact. 2014 Apr 5;212:65-71. doi: 10.1016/j.cbi.2014.01.013. Epub 2014 Feb 1.

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.

Keywords: Antioxidation; Apoptosis; Doxorubicin; Hepatotoxicity; NAD(+).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / administration & dosage
  • Acetylcysteine / pharmacology
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antioxidants / metabolism*
  • Apoptosis / drug effects
  • Aspartate Aminotransferases / blood
  • Body Weight / drug effects
  • Cytoprotection / drug effects*
  • DNA Damage*
  • Doxorubicin / adverse effects*
  • Liver / anatomy & histology
  • Liver / cytology
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • NAD / administration & dosage*
  • NAD / metabolism
  • NAD / pharmacology*
  • Organ Size / drug effects

Substances

  • Antineoplastic Agents
  • Antioxidants
  • NAD
  • Doxorubicin
  • Aspartate Aminotransferases
  • Acetylcysteine