APE1/REF-1 down-regulation enhances the cytotoxic effects of temozolomide in a resistant glioblastoma cell line

Publication date: Available online 5 June 2015 Source:Mutation Research/Genetic Toxicology and Environmental Mutagenesis Author(s): Ana P. Montaldi , Paulo R.D.V. Godoy , Elza T. Sakamoto-Hojo Temozolomide (TMZ) is widely used for patients with glioblastoma (GBM); however, tumor cells frequently exhibit drug-resistance. Base excision repair (BER) has been identified as a possible mediator of TMZ resistance, and an attractive approach to sensitizing cells to chemotherapy. Human apurinic/apyrimidinic endonuclease/redox factor-1 (APE1) is an essential enzyme with a role in the BER pathway by repairing abasic sites, and it also acts as a reduction factor, maintaining transcription factors in an active reduced state. Thus, we aimed to investigate whether the down-regulation of APE1 expression by siRNA can interfere with the resistance of GBM to TMZ, being evaluated by several cellular and molecular parameters. We demonstrated that APE1 knockdown associated with TMZ treatment efficiently reduced cell proliferation and clonogenic survival of resistant cells (T98G), which appears to be a consequence of increased DNA damage, S-phase arrest, and H2AX phosphorylation, resulting in apoptosis induction. On the contrary, for those assays, the sensitization effects of APE1 silencing plus TMZ treatment did not occur in the TMZ-sensitive cell line (U87MG). Interestingly, TMZ-treatment and APE1 knockdown significantly reduced cell invasion in both cell lines, but TMZ alone did not reduc...
Source: Mutation Research Genetic Toxicology and Environmental Mutagenesis - Category: Genetics & Stem Cells Source Type: research