Galactosyl derivative of N(omega)-nitro-L-arginine: study of antiproliferative activity on human thyroid follicular carcinoma cells.

Full Abstract

The methyl ester prodrug of N(omega)-nitro-L-arginine (L-NAME) has been reported to exert anticancer effects against several human tumors, including thyroid carcinoma, by inhibiting nitric oxide synthase (NOS). However, chronic administration of L-NAME has often led to adverse events causing cardiovascular alterations due to its potential toxic effect. Here we report for the first time the synthesis of the galactosyl ester prodrug of N(omega)-nitro-L-arginine, NAGAL, a prodrug capable of inhibiting NOS more efficiently and with fewer adverse events than its parent drug. For this purpose RO82-W-1, a thyroid cell line derived from human follicular carcinoma, was used. MTT test results showed that NAGAL affected cell viability to a significantly greater extent than did L-NAME. Moreover, fluorescence activated cell sorter (FACS) analyses revealed that NAGAL, compared to L-NAME, was able to reduce nitric oxide (NO) production as well as increase the percentage of apoptotic thyreocytes. Western blot further confirmed the reduction in NOS-II expression by NAGAL. Finally, by using the LC-MS technique, we found that NAGAL elicited a higher increase in N(omega)-nitro-L-arginine (NA) concentration than did L-NAME. Thus, this study suggests that NAGAL could be considered a potential therapeutic tool for those pathologies involving an overproduction of NO, including thyroid carcinoma.

Author information

Author/s: Melisi, Daniela (D); Rosso, Francesco (F); Curcio, Annalisa (A); Tortora, Carla (C); Nieddu, Maria (M); Marino, Gerardo (G); Lettieri, Maria (M); Grimaldi, Anna (A); Luongo, Elvira (E); Romano, Simona (S); Romano, Maria Fiammetta (MF); Boatto, Gianpiero (G); Abignente, Enrico (E); Barbarisi, Alfonso (A); Rimoli, Maria Grazia (MG);

Affiliation: Faculty of Pharmacy, Department of Pharmaceutical and Toxicological Chemistry, Federico II University of Naples, Naples, Italy. melisi(-atsign-)unina.it

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of cellular physiology (J Cell Physiol), published in United States. (Language: eng)

Reference: 2009-Nov; vol 221 (issue 2) : pp 440-7

Dates: Created 2009/08/27; Completed 2009/09/09;

PMID: 19650107, status: MEDLINE (last retrieval date: 9/9/2009, IMS Date: )

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