title: Cytotoxic and proapototic activities of imidoselenocarbamate derivatives are dependent on the release of methylselenol.
abstract: In the search for new molecules with potential antiangiogenic activity, we found that several imidoselenocarbamate derivatives effectively suppressed the expression of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI-H157 tumor cells. Mechanistic studies indicated that these compounds inhibited STAT3 phosphorylation triggered by hypoxia, suggesting that inhibition of STAT3 function may play a role in VEGF inhibition. Moreover, these molecules showed interesting proapoptotic and antiproliferative effects. Both the presence of selenium, but not sulfur, and the nature of the radical substituents were important for activity. Interestingly, under hypoxic conditions, several methyl imidoselenocarbamate derivatives released methylselenol, a highly reactive and cytotoxic gas, which was responsible for their biological activities. The kinetics of the release of methylselenol by these molecules was highly dependent on the nature of the substituent radicals and correlated with their early proapoptotic activity. Our results support the notion that pharmacological activities reported for methyl imidoselenocarbamate derivatives are dependent on the release of methylselenol. Given the well-known antitumor activities of this compound, imidoselenocarbamate derivatives represent a promising approach to develop new drugs that release methylselenol in a controlled way.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Zuazo
authors.forename: Daniel
authors.initials: D
authors.lastname: Plano
authors.forename: Elena
authors.initials: E
authors.lastname: Ansó
authors.forename: Elena
authors.initials: E
authors.lastname: Lizarraga
authors.forename: María
authors.initials: M
authors.lastname: Font
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Martínez Irujo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016566:Organoselenium Compounds