Improvements of Doxorubicin-Induced Antitumor Activity and Adverse Reaction by Combined Citrulline

Abstract

Citrulline is an amino acid with antioxidant activity. In this study, effects of citrulline on the adverse effects of doxorubicin (DOX) and DOX-induced antitumor activity were examined. Citrulline significantly inhibited DOX-induced increases in lipid peroxide (LPO) in the heart as adverse reaction. Combined treatment with DOX and citrulline increased DOX levels in tumor cells and enhanced cytotoxicity in vitro by significantly increasing DOX uptake compared with DOX treatment alone. In simultaneous in vivo treatments, combination treatment with DOX and citrulline decreased tumor weight and increased DOX concentrations in tumors. Promotion of DOX uptake by citrulline enhanced the antitumor activity of DOX through the action of energy-independent and Na(+)-independent transporters. This effect of citrulline on DOX influx is identical to that of S-(4-nitrobenzyl)-6-thioinosine, promoting DOX influx through the equilibrative nucleoside transporter 1. Therefore, it is anticipated that citrulline as a food component may enhance DOX efficacy.