Synergistic Effects of Curcumin and Temozolomide in Overcoming Glioblastoma Drug Resistance through Regulation of O6-Methylguanine-DNA Methyltransferase, Mismatch Repair, and Poly(Adenosine Diphosphate Ribose) Polymerase 1.

Abstract

Background and objective: Glioblastoma is one of the most frequently seen cancer types in the central nervous system, which is associated with drug resistance and high mortality rates. Curcumin demonstrates significant anticancer potential by inhibiting crucial processes, such as cell proliferation and metastasis, positioning it as a candidate for targeted treatment strategies. In this study, the potential of curcumin to overcome temozolomide resistance in U87 glioblastoma cells was examined, with a focus on elucidating the underlying molecular pathways.

Methods: U87 and U87/TMZ cells were treated with different concentrations of curcumin, temozolomide, and their combination for 24 and 48 hours, and the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to assess viability. The expression of key genes and proteins of the Bax, Bcl-2, caspase-3, O6-methylguanine-DNA methyltransferase, and DNA repair genes, including MSH2, MSH6, and PARP1, was evaluated by quantitative real-time polymerase chain reaction and western blot. Also, the activity of caspase-3/7 enzymes and the level of apoptosis were measured by fluorometric methods and enzyme-linked immunosorbent assay.

Results: Curcumin significantly decreased temozolomide-resistant U87 cell viability in combination with temozolomide in a dose-dependent manner. The expression of O6-methylguanine-DNA methyltransferase, MSH2, MSH6, and PARP1 genes and proteins was decreased. Also, the increase in Bax expression and caspase activity indicated a strong induction of apoptosis by curcumin in resistant cells.

Conclusions: Curcumin mitigates temozolomide resistance in glioblastoma by modulating the O6-methylguanine-DNA methyltransferase/MSH2/MSH6 axis and enhancing apoptosis. This natural compound holds promise as a potential agent for the development of targeted glioblastoma therapies.