title: A glycosylated nitric oxide donor, beta-Gal-NONOate, and its site-specific antitumor activity.
abstract: 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.
authors.affiliation: State Key Laboratory of Microbial Technology, Shandong University, Jinan, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Chen
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Shi
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Qi
authors.forename: Li
authors.initials: L
authors.lastname: Gu
authors.forename: Jing
authors.initials: J
authors.lastname: Song
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: 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
chemical_list: 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