Modulation of selenium-dependent glutathione peroxidase activity enhances doxorubicin-induced apoptosis, tumor cell killing, and hydroxyl radical production in human NCI/ADR-RES cancer cells despite high-level P-glycoprotein expression.
Free Radic Res. 2019 Jul 10:1-311. Epub 2019 Jul 10. PMID: 31290351
James H Doroshow
To define the role of glutathione peroxidase (GPx) in modulating the oxygen radical-related cytotoxicity of doxorubicin and HOin cells that overexpress P-glycoprotein (Pgp), the GPx activity of NCI/ADR-RES cancer cells was altered by growth in 0.5% serum with (MR-30 subline) or without (MR-0 subline) selenium supplementation. GPx activity increased from 2.2 nmol/min/mg (MR-0) to 22.5 nmol/min/mg (MR-30) when cells were grown in 30-nM selenium, < 0.01; the activities of other antioxidant enzymes were unchanged by selenium. By reverse transcriptase polymerase chain reaction (RT-PCR), MR-30 and MR-0 cells expressed similar levels of the1,, andmRNA. The ICconcentration for HOin MR-0 cells was ten-fold lower than in the MR-30 subline, < 0.01. Despite identical anthracycline accumulation and efflux in these two lines that expressed equivalent levels of Pgp, the doxorubicin ICdecreased 5-fold in MR-0 vs. MR-30 cells, < 0.01. Log-linear tumor cell killing by doxorubicin was observed only in selenium-deficient MR-0 cells. Doxorubicin exposure also produced substantially more apoptosis in MR-0 than MR-30 cells; this was not related to the presence of selenium. MR-0 cells generated≈5-times more methane from dimethyl sulfoxide (a measure of reactive oxygen metabolism) than MR-30 cells in the presence of equimolar doxorubicin concentrations ( < 0.05). These studies suggest that GPx-mediated detoxification of peroxides can modulate the antitumor activity of doxorubicin in the presence of high levels of Pgp.