Galactosyl derivative of N(omega)-nitro-L-arginine: study of antiproliferative activity on human thyroid follicular carcinoma cells.
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.
Melisi
Daniela
D
Faculty of Pharmacy, Department of Pharmaceutical and Toxicological Chemistry, Federico II University of Naples, Naples, Italy. melisi@unina.it
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
D018263:Adenocarcinoma, Follicular / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D005690:Galactose / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D019335:Nitroarginine / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000473:pathology*; D013997:Time Factors
D019335:Nitroarginine; D009569:Nitric Oxide; D005690:Galactose