A glycosylated nitric oxide donor, beta-Gal-NONOate, and its site-specific antitumor activity.
So far, nitric oxide (NO) donors have been applied to various aspects of antitumor therapy. To selectively sensitize tumor cells and avoid unwanted side effects, we recently synthesized a beta-galactosidase-activatable NO-releasing compound, beta-galactosyl-pyrrolidinyl diazeniumdiolate (beta-Gal-NONOate). In this study, we first verified its superiority over its parent diazeniumdiolate (NONOate) in terms of targeted intracellular NO-releasing and antitumor activity with 9L/LacZ cells (rat glioma cell line 9L with transformed LacZ gene) in vitro. beta-Gal-NONOate only released NO when hydrolyzed by induced beta-galactosidase in 9L/LacZ cells, which led to its more powerful cytotoxicity than that of NONOate. The results showed that beta-Gal-NONOate produced higher NO levels than NONOate in 9L/LacZ cells at equal concentration, and hence induced optimal NO levels for antitumor activity. However, in 9L cells, beta-Gal-NONOate showed less toxicity than NONOate. Therefore, it is demonstrated that beta-Gal-NONOate is a site-specific prodrug for targeting NO intracellularly as a beta-galactosidase-sensitive NO donor, and it is also expected to be a promising probe in numerous experimental settings and a potential therapeutic drug for antitumor treatment.
Chen
Chang
C
State Key Laboratory of Microbial Technology, Shandong University, Jinan, China.
Shi
Yanqiu
Y
Li
Song
S
Qi
Qingsheng
Q
Gu
Li
L
Song
Jing
J
Wang
Peng George
PG
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005690:Galactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D005697:Galactosides / Q000494:pharmacology; D006031:Glycosylation; D007211:Indoles / Q000494:pharmacology; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013194:Staining and Labeling / Q000379:methods; D001616:beta-Galactosidase / Q000378:metabolism
D000970:Antineoplastic Agents; D001391:Azo Compounds; D005697:Galactosides; D007211:Indoles; D020030:Nitric Oxide Donors; C514571:beta-Gal-NONOate; C452539:diazeniumdiolate; D009569:Nitric Oxide; D001616:beta-Galactosidase; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside; D005690:Galactose