Human Glioma Cells Acquire Temozolomide Resistance After Repeated Drug Exposure Via DNA Mismatch Repair Dysfunction

Abstract

Background/aim: Temozolomide (TMZ) induces prolonged arrest of human glioma cells in the G₂/M phase and inhibition of the G₂ checkpoint intensifies the effect of TMZ. These findings suggest that the G₂ checkpoint is linked to DNA repair mechanisms.

Materials and methods: To clarify the mechanism of TMZ resistance, we established TMZ-resistant (TR) clones by serial treatment of U87MG cells with TMZ. We evaluated TMZ-induced cell cycle arrest and the effect of various G₂ checkpoint inhibitors.

Results: We observed that longer exposure (over 6 months) to TMZ enriched the proportion of TR clones that underwent only minimal G₂ arrest following TMZ treatment compared to short exposure (4 months) to TMZ. Expression of MSH6 was reduced in these clones. None of the G₂ checkpoint inhibitors could resensitize TR clones to TMZ.

Conclusion: Longer drug treatment may induce resistance of cells to DNA damaging agent(s) by means of mismatch repair modification.

Keywords: DNA mismatch repair; G2 checkpoint; Temozolomide; glioblastoma; resistance.