Aristi Fernandes Group

Research Projects

It has become evident that tumor cells are particularly sensitive to oxidative stress as they have persistently higher levels of reactive oxygen species (ROS) than normal cells due to dysregulation of the redox balance. Owing to the increased ROS production, tumor cells adapt and upregulate their antioxidant defense, this however leaves little room for further compensation in case of an additional ROS induction. The vulnerability of some cancer cells to oxidative stress is a therapeutic target and has evolved as the rational design of new anticancer agents. Among them, redox active selenium derivatives (SeD) have gained substantial attention due to their promising chemotherapeutic potential. The focus of the research is mechanistical investigation of redox modulations by SeD and other redox modulating compounds on a molecular and biochemical level. In relation to this, we are studying the glutaredoxin and thioredoxin systems that exhibit an important role in the cellular protection against oxidative stress by reduction of thiols. A deeper insight of these redox systems would lead to increased understanding of the physiological redox control in normal and cancer cells. Hence, the project aims in exploring and taking advantage of the redox Achilles heel of cancer cells, by achieving to develop novel compounds that exhibits a potent ability to promote ROS generation predominantly in cancer cells, and identifying new delivery systems that selectively release the drug in the site of action. The overall goal of the research group is thus to mechanistically understand and to develop new approaches by redox modification in the treatment of resistant tumors.

Selected publications

Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death.
Arodin L, Miranda-Vizuete A, Swoboda P, Fernandes A
Free Radic. Biol. Med. 2014 Aug;73():328-36

Selenium induces a multi-targeted cell death process in addition to ROS formation.
Wallenberg M, Misra S, Wasik A, Marzano C, Björnstedt M, Gandin V, et al
J. Cell. Mol. Med. 2014 Apr;18(4):671-84

Methylselenol formed by spontaneous methylation of selenide is a superior selenium substrate to the thioredoxin and glutaredoxin systems.
Fernandes A, Wallenberg M, Gandin V, Misra S, Tisato F, Marzano C, et al
PLoS ONE 2012 ;7(11):e50727

Effects of redox modulation by inhibition of thioredoxin reductase on radiosensitivity and gene expression.
Selenius M, Hedman M, Brodin D, Gandin V, Rigobello M, Flygare J, et al
J. Cell. Mol. Med. 2012 Jul;16(7):1593-605

Selenium compounds are substrates for glutaredoxins: a novel pathway for selenium metabolism and a potential mechanism for selenium-mediated cytotoxicity.
Wallenberg M, Olm E, Hebert C, Björnstedt M, Fernandes A
Biochem. J. 2010 Jul;429(1):85-93

Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase.
Gandin V, Fernandes A, Rigobello M, Dani B, Sorrentino F, Tisato F, et al
Biochem. Pharmacol. 2010 Jan;79(2):90-101

Extracellular thiol-assisted selenium uptake dependent on the x(c)- cystine transporter explains the cancer-specific cytotoxicity of selenite.
Olm E, Fernandes A, Hebert C, Rundlöf A, Larsen E, Danielsson O, et al
Proc. Natl. Acad. Sci. U.S.A. 2009 Jul;106(27):11400-5

Expression profiles of thioredoxin family proteins in human lung cancer tissue: correlation with proliferation and differentiation.
Fernandes A, Capitanio A, Selenius M, Brodin O, Rundlöf A, Björnstedt M
Histopathology 2009 Sep;55(3):313-20