title: Selenium induces a multi-targeted cell death process in addition to ROS formation.
abstract: Selenium compounds inhibit neoplastic growth. Redox active selenium compounds are evolving as promising chemotherapeutic agents through tumour selectivity and multi-target response, which are of great benefit in preventing development of drug resistance. Generation of reactive oxygen species is implicated in selenium-mediated cytotoxic effects on cancer cells. Recent findings indicate that activation of diverse intracellular signalling leading to cell death depends on the chemical form of selenium applied and/or cell line investigated. In the present study, we aimed at deciphering different modes of cell death in a single cell line (HeLa) upon treatment with three redox active selenium compounds (selenite, selenodiglutathione and seleno-DL-cystine). Both selenite and selenodiglutathione exhibited equipotent toxicity (IC50 5 μM) in these cells with striking differences in toxicity mechanisms. Morphological and molecular alterations provided evidence of necroptosis-like cell death in selenite treatment, whereas selenodiglutathione induced apoptosis-like cell death. We demonstrate that selenodiglutathione efficiently glutathionylated free protein thiols, which might explain the early differences in cytotoxic effects induced by selenite and selenodiglutathione. In contrast, seleno-DL-cystine treatment at an IC50 concentration of 100 μM induced morphologically two distinct different types of cell death, one with apoptosis-like phenotype, while the other was reminiscent of paraptosis-like cell death, characterized by induction of unfolded protein response, ER-stress and occurrence of large cytoplasmic vacuoles. Collectively, the current results underline the diverse cytotoxic effects and variable potential of redox active selenium compounds on the survival of HeLa cells and thereby substantiate the potential of chemical species-specific usage of selenium in the treatment of cancers.
authors.affiliation: Division of Pathology F46, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Marita
authors.initials: M
authors.lastname: Wallenberg
authors.forename: Sougat
authors.initials: S
authors.lastname: Misra
authors.forename: Agata M
authors.initials: AM
authors.lastname: Wasik
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Mikael
authors.initials: M
authors.lastname: Björnstedt
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Aristi P
authors.initials: AP
authors.lastname: Fernandes
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006367:HeLa Cells; D006801:Humans; D016566:Organoselenium Compounds / Q000008:administration & dosage*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012643:Selenium / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C017710:selenodiglutathione; D005978:Glutathione; D012643:Selenium
keywords: ER-stress; Selenium compounds; cell death; glutathionylation; reactive oxygen species