Contribution of nitric oxide in doxorubicin - related cytotoxicity in murine tumour model

Abstract EN

Background : doxorubicin (DOX) is an anthracycline antibiotic with broad spectrum antineoplastic activity against different types of experimental and human tumours.

However, the optimal usefulness of this important anticancer drug has been limited due to the development of tumour cell drug resistance.

Several anticancer drugs including cisplatin, hydroxyurea and DOX have been shown to stimulate nitric oxide (NO) production, which has been demonstrated to affect several aspects of tumour biology.

Purpose : this study has been initiated to determine if DOX stimulates NO production in EAC-cells and if so, whether NO interferes with p-glycoprotein (p-gp) function and to determine if DOX-stimulated NO production contributes to DOX's cytotoxicity in vivo against solid Ehrlich carcinoma (SEC).

Materials and methods : to achieve these goals, the in vitro and in vivo effects of DOX and the nitric oxide syn-thase (NOS) inhibitors, aminoguanidine (AG) and NG-nitro-L-arginine-methyl ester (L-NAME) on the growth of SEC, NO production, rhodamine 123 (RD 123) accumulation and endothelial nitric oxide synthase (eNOS) were studied in EAC-cells.

Results : A single dose of DOX (10 mg / kg i.p.) resulted in significant decrease in tumour volume and significant increase in serum NO level.

Administration of AG (100 mg / kg i.p.), or L-NAME (100 mg / kg i.p.) one hour prior to DOX, significantly decreased DOX-induced NO production and attenuated doxorubicin's effect on tumour volume.

Treatment with L-NAME or AG alone induced an insignificant change in NO production.

Incubation of EAC-cells with AG or L-NAME resulted in significant decrease in NO production, endothelial nitric oxide synthase (eNOS) activity and RD 123 accumulation.

The addition of AG or L-NAME to DOX-incubated cells resulted in significant decrease in NO production and RD 123 accumulation compared to DOX alone.

Conclusion : this study suggests that NO may contribute to DOX's antitumour activity.

Increased NO production by DOX may decrease p-gp function with the consequent increase in DOX accumulation in EAC-cells.

Further studies are needed to confirm these findings.