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.Key words citrulline; doxorubicin; adverse reaction; antitumor activity; doxorubicin permeability Currently, cancer therapies include surgery, radiation therapy, and chemotherapy, which is appropriate for hematological tumors and general metastases. Among cancer chemotherapies, alkylating agents, antimetabolites, plant alkaloids, antitumor antibiotics platinum compounds, and molecular targeting agents are used. Furthermore, because mechanisms of antitumor agents vary, combined therapies offer clinical potential to enhance antitumor activity and reduce adverse reactions. [1][2][3][4][5] In contrast, while some biochemical modulators without antitumor activity enhance the pharmacological properties of antitumor agents, these can improve the therapeutic indexes or ameliorate adverse reactions by antitumor agents. However, these therapies often enhance antitumor agent induced adverse reactions with the increase in antitumor activity. Hence, developments and discoveries of novel modulators that enhance antitumor activities and reduce adverse reactions to antitumor agents are required.The anthracycline doxorubicin (DOX) is widely used to treat a variety of malignancies, despite the severity of associated adverse reactions, such as cardiotoxicity. Although many studies report enhancement of DOX antitumor activity in tumor cells by direct inhibition of DOX efflux, no agents or combinations have been found to increase the therapeutic index of DOX by expression of these efflux pumps in normal tissues. Previously, we reported improved DOX-induced antitumor activity using the food components caffeine, theanine, and cucurbitacins. [6][7][8][9][10][11][12][13][14][15] It appeared that these effects were mediated by increased DOX concentration in the tumors, which suppress DOX efflux from tumor cells. In contrast, linalool promoted DOX influx into tumor cells and enhanced its activity by acting on the Na + -dependent nucleoside transporter (CNT) 3.16) Furthermore, decreases in DOX levels following...

Metabonomic Study of the Effects of Acanthopanax senticosus on Peripheral System of Rats

“…NO deficiency mediates oxidative stress in the kidney and is involved in the development of hypertension [35]. In the present study, AS increased the levels of citrulline in this tissue, which has antioxidant activity and acts as an NO precursor to increase NO production [35][36][37]. The upregulation of tetrahydropteridine by AS may enhance the function of citrulline, which is involved in oxidative stress as a regulator of NO synthase or as a direct radical scavenger [38].…”

Tissue metabolic profiling of human gastric cancer assessed by 1H NMR

“…Citrulline, a naturally non-essential amino acid, was firstly found in watermelon, Apart from its role in protein homeostasis and as an intermediate in urea cycle, citrulline is also found to be a potent hydroxyl radical scavenger and much more effective precursor of arginine and NO than arginine itself [ 45 , 46 ]. The level of citrulline decreased along with the processes of gastric cancer, which may suggest the deterioration of the redox state of tumor.…”