Toma stem (brain-tumor-initiating) cells [12] and human glioblastoma cell lines [58]. Notably, in
Toma stem (brain-tumor-initiating) cells [12] and human glioblastoma cell lines [58]. Notably, within the latter study, only 1 (U138MG) and in tendency also a second (T98G) out of 5 glioblastoma lines were radiosensitized by disulfiram (7500 nM) when grown in Cu2+ -containing serum-supplemented medium and when making use of clonogenic survival because the p38 MAPK Inhibitor review endpoint [58]. Clonogenic survival determines the probability of a treated tumor to relapse, and is consequently believed to be the gold common for the interpretation of drug effects on radiosensitivity in radiation biology [59]. In the glioblastoma stem-cell spheroid cultures, five Gy irradiation in mixture with disulfiram (one hundred nM) and Cu2+ (200 nM) further decreased viability (as defined by metabolic activity and when compared with the disulfiram/Cu2+ /0 Gy arm) of only 1 out of two tested spheroid cultures [12]. Also, in the exact same study, disulfiram/Cu2+ delayed repair of DNA double-strand breaks (DSBs) of 2 Gy-irradiated cells without having escalating the number of residual (24 h-value) DSBs, as analyzed by the counting of nuclear H2AX (αLβ2 Inhibitor Compound phosphorylated histone H2AX) foci [12]. Because only limited conclusions on clonogenic survival could be drawn in the decay of radiation-induced H2AX foci [60] too as metabolically defined “viability” of irradiated cancer cells, the reported evidence to get a radiosensitizing function of disulfiram in glioblastoma stem cells is restricted. Combined with the notion that disulfiram radiosensitized only a minor fraction in the tested panel of glioblastoma cell lines [58], and moreover thinking about the results of our present study, it might be concluded that disulfiram may perhaps radiosensitize glioblastoma (stem) cells, but this appears to be rather an exception than a basic phenomenon. The predicament is distinctive in irradiated AT/RT (atypical teratoid/rhabdoid) brain tumor lines and main cultures, exactly where disulfiram (in Cu(II)-containing serum-supplemented medium) regularly decreases survival fractions in colony formation assays of all tested cell models with an EC50 of 20 nM [61]. 4.three. Cu2+ -Mediated Oxidative Strain The radiosensitizing action of disulfiram in all probability depends upon the Cu2+ ion-overloading function of your drug. Ionizing radiation induces beyond instant radical formation (e.g., formation of OHby ionization of H2 O) delayed long-lasting mitochondrial-generated superoxide anion (O2 – formation which contributes to radiation-mediated genotoxic damage [62]. It is tempting to speculate that disulfiram-mediated Cu2+ overload and subsequent OHformation (see introduction) collaborates with radiation-triggered mitochondrial oxidative strain (and also with temozolomide) in introducing DNA DSBs. If so, the radiosensitizing (as well as temozolomide-sensitizing) effect of disulfiram needs to be, on the one particular hand, a direct function with the interstitial Cu2+ concentration, and around the other, a function from the intracellular Cu2+ -reducing, Cu+ -chaperoning, -sequestrating, and -extruding capability also because the oxidative defense of a tumor cell [63,64]. The Cu2+ -Biomolecules 2021, 11,17 ofdetoxifying capability most most likely differs amongst cell kinds, and may possibly explain the difference in reported radiosensitizing activity of disulfiram between AT/RT [61] plus the glioblastoma (stem) cells ([12,59] and present study). In unique, tumor stem cells have been demonstrated to exhibit upregulated drug-efflux pumps, DNA repair, and oxidative defense [65]. 4.four. Does Disulfiram Specificall.
