2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche

Abstract

Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also accumulate in hypoxic cells, where they can act as cytotoxins or imaging agents. However, whether these effects apply to cancer stem cells has not been sufficiently explored. Here we show that the 2-nitroimidazole doranidazole potentiates radiation-induced DNA damage in hypoxic glioma stem cells (GSCs) and confers a significant survival benefit in mice harboring GSC-derived tumors in radiotherapy settings. Furthermore, doranidazole and misonidazole, but not metronidazole, manifested radiation-independent cytotoxicity for hypoxic GSCs that was mediated by ferroptosis induced partially through blockade of mitochondrial complexes I and II and resultant metabolic alterations in oxidative stress responses. Doranidazole also limited the growth of GSC-derived subcutaneous tumors and that of tumors in orthotopic brain slices. Our results thus reveal the theranostic potential of 2-nitroimidazoles as ferroptosis inducers that enable targeting GSCs in their hypoxic niche.

Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways

“…The effect of radiation exposure on prostate cancer cells was analyzed as previously described 12 . X-ray irradiation was delivered using an MBR-1520R-4 system (Hitachi Power Solutions, Ibaraki, Japan) at settings of 150 kV and 20 mA.…”

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

“…In colorectal CSCs, knockdown or inhibition of SLC7A11 significantly and specifically kills cancer cells and thus attenuates chemoresistance in CRC ( Xu et al, 2020c ). Besides, two nitroimidazoles ( Koike et al, 2020 ), itraconazole ( Xu et al, 2021 ), and dichloroacetate ( Sun et al, 2021 ) are also proven to have therapeutic potential through promoting ferroptosis in CSCs.…”

Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells

“…We found this glucose concentration to be 0.175 mM, which corresponds to 1% of the concentration in our standard culture condition. We have previously shown that GSCs can differ in their main energy pathway, and have established two clonal GSC populations, glycolytic GSCs (GSC gly , line GSCA), and oxidative GSCs (GSC mit , line GSCB) [ 12 ], as well as a non-clonal population containing predominantly oxidative GSCs (TSH) [ 12 , 24 ]. Here, we first cultured GSCA and GSCB in in a medium containing 0.175 mM glucose (ultralow glucose medium, or ULGM) and various concentrations of lactate ( Figure 1 A).…”

“…The GSCs used in our study were established by transformation of neural stem/progenitor cells with the oncoprotein H-Ras V12 [ 12 , 24 , 30 ]. Given that neuronal stem cells are able to survive on lactate for up to 24 h [ 22 ], the ability of GSCs to use lactate might reflect a characteristic of their cell of origin.…”

“…The clonal GSC lines GSCA and GSCB were derived from murine Ink4a/Arf -null neural stem/progenitor cells expressing the fluorescent protein ds-Red and H-Ras V12 (glioma-initiating cells, GIC-A and GIC-B) and were established as previously described [ 12 , 31 ]. TSH is a stem cell line derived after one passage in vivo from GIC-H cells (sorted by hygromycin selection) [ 12 , 24 ]. TSH-N1 to TSH-N10 cells were established by single-cell cloning from the TSH line.…”