Cytotoxic mechanisms of selenium in cancer

Selenium is an essential trace element with a diverse number of functions in the body as part of multiple selenoproteins. Acknowledged for its cancer preventive properties in clinical trials, selenium has in recent years also evolved as a potential chemotherapeutic agent. This notion is based on the vast observations supporting that selenium compounds can induce cell death in cancer cells at dose levels harmless to non-neoplastic cells.

In this thesis, the selenium compound selenite (SeO32-) was explored and evaluated as a potential chemotherapeutic drug. The aim was to understand how selenite targets cancer cells but not benign cells and why some cancers are more sensitive to selenite than others. To assess this we explored mechanisms behind selenium uptake and retention, effects on intracellular redox systems and apoptotic pathways. Selenite toxicity was furthermore compared to conventional drugs to investigate possible patterns of cross resistance.

The results suggest that selenite toxicity is dependent on a high affinity uptake of selenium reliant on extracellular reduction of selenite by cancer cells. The reductive capacity of the extracellular microenvironment was determined by cystine uptake through the xc-cystine transporter and secretion of cysteine through multiresistance protein pumps. Selenite toxicity conferred suppression of redox protein TrxR1 expression but induced redox protein Grx1 expression. The Grx1 protein was furthermore concluded to encompass a pro-toxic role in selenite cytotoxicity. Selenite induced apoptosis through the mitochondrial pathway independent of p53 DNA binding activity and was robust to inhibition of apoptotic key molecules. Comparison of selenite toxicity to other drugs showed no sign of cross resistance.

Taken together, the results suggest that selenite is a potent anticancer drug with an elevated specificity toward the drug resistant phenotype and that selenite should further be investigated through clinical trials.

List of scientific papers

I. Olm E, Jönsson-Videsäter K, Ribera-Cortada I, Fernandes AP, Eriksson LC, Lehmann S, Rundlöf AK, Paul C, Björnstedt M (2009). Selenite is a potent cytotoxic agent for human primary AML cells. Cancer Lett. 282(1): 116-23. Epub 2009 Apr 3
https://pubmed.ncbi.nlm.nih.gov/19345479

II. Nilsonne G, Olm E, Szulkin A, Mundt F, Stein A, Kocic B, Rundlöf AK, Fernandes AP, Björnstedt M, Dobra K (2009). Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure. J Exp Clin Cancer Res. 28: 92
https://pubmed.ncbi.nlm.nih.gov/19563663

III. Olm E, Fernandes AP, Hebert C, Rundlöf AK, Larsen EH, Danielsson O, Björnstedt M (2009). Extracellular thiol-assisted selenium uptake dependent on the x(c)- cystine transporter explains the cancer-specific cytotoxicity of selenite. Proc Natl Acad Sci USA. 106(27): 11400-5. Epub 2009 Jun 22
https://pubmed.ncbi.nlm.nih.gov/19549867

IV. Wallenberg M, Olm E, Hebert C, Björnstedt M, Fernandes AP (2009). Selenium compounds are substrates for glutaredoxins: A novel pathway for selenium metabolism and a potential mechanism for selenium mediated cytotoxicity. [Manuscript]