Inhibition of GSH synthesis potentiates temozolomide-induced bystander effect in glioblastoma

TMZ-induced bystander effects were not observed in tumors with 50% MGMT positivity.

• TMZ-resistant GBM cells were generated by introducing a DNA repair enzyme, MGMT, into a TMZ-sensitive cell line.
• Bystander effects of TMZ-induced cell death were not evident in tumors with high MGMT levels (50%).
• In tumors with low MGMT positivity (1%), bystander effects were observed within 20 days, but final tumor sizes were similar to controls without sensitive cells.
• Conditioned medium from TMZ-damaged GBM cells activated stress and toxicity pathways and increased the expression of antioxidant genes in TMZ-resistant cells.
• Inhibiting GSH synthesis enhanced the bystander effect in TMZ-resistant cells, suggesting potential for combination therapy.

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