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, inside the latter study, only one particular (U138MG) and in tendency also a second (T98G) out of five glioblastoma lines have been radiosensitized by disulfiram (7500 nM) when grown in Cu2+ -containing serum-supplemented medium and when employing clonogenic survival because the endpoint [58]. Clonogenic survival determines the probability of a treated tumor to relapse, and is consequently believed to become the gold typical for the interpretation of drug effects on radiosensitivity in radiation biology [59]. Inside the glioblastoma stem-cell spheroid cultures, five Gy irradiation in mixture with disulfiram (100 nM) and Cu2+ (200 nM) additional decreased viability (as defined by metabolic activity and in comparison to the disulfiram/Cu2+ /0 Gy arm) of only one out of two tested spheroid cultures [12]. Moreover, inside the exact same study, disulfiram/Cu2+ delayed repair of DNA double-strand breaks (DSBs) of two Gy-irradiated cells without the need of increasing the number of residual (24 h-value) DSBs, as analyzed by the counting of nuclear H2AX (phosphorylated histone H2AX) foci [12]. Due to the fact only limited conclusions on clonogenic survival is often drawn from the decay of radiation-induced H2AX foci [60] as well 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 all the notion that disulfiram radiosensitized only a minor mGluR1 Activator list fraction of your tested panel of glioblastoma cell lines [58], and also taking into consideration 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 general phenomenon. The circumstance is different in irradiated AT/RT (atypical teratoid/rhabdoid) brain tumor lines and major cultures, where disulfiram (in Cu(II)-containing serum-supplemented medium) consistently decreases survival fractions in colony formation assays of all tested cell models with an EC50 of 20 nM [61]. 4.three. Cu2+ -Mediated Oxidative Stress The radiosensitizing action of disulfiram almost certainly depends upon the Cu2+ ion-overloading function in the drug. Ionizing radiation induces beyond immediate 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 harm [62]. It really is NPY Y1 receptor Agonist custom synthesis tempting to speculate that disulfiram-mediated Cu2+ overload and subsequent OHformation (see introduction) collaborates with radiation-triggered mitochondrial oxidative anxiety (and also with temozolomide) in introducing DNA DSBs. If that’s the case, the radiosensitizing (as well as temozolomide-sensitizing) impact of disulfiram needs to be, on the 1 hand, a direct function from the interstitial Cu2+ concentration, and on the other, a function from the intracellular Cu2+ -reducing, Cu+ -chaperoning, -sequestrating, and -extruding capability at the same time because the oxidative defense of a tumor cell [63,64]. The Cu2+ -Biomolecules 2021, 11,17 ofdetoxifying capability most probably differs amongst cell forms, and could possibly explain the difference in reported radiosensitizing activity of disulfiram in between AT/RT [61] and the glioblastoma (stem) cells ([12,59] and present study). In distinct, tumor stem cells have already been demonstrated to exhibit upregulated drug-efflux pumps, DNA repair, and oxidative defense [65]. four.4. Does Disulfiram Specificall.
