The role of leptin and leptin receptor antagonist on temozolomide resistance i̇n glioblastoma

Glioblastoma (GB) is the most malignant brain tumor. GB is often resistant to radiotherapy and chemotherapy treatment in terms of molecular and clinical features. Temozolomide (TMZ) is the most common drug as chemotherapy. Recent studies have indicated that leptin may play a role in chemotherapeutic resistance to cancer treatment. In this thesis; We aimed to investigate the possible role of leptin and/or leptin antagonist (SHLA) in chemotherapeutic resistance to TMZ in GB. T98G, U373 MG and LN405 GB cell lines were used in this study. The cytotoxicity of TMZ, leptin, and SHLA was determined by MTT. The effect of single use of TMZ, leptin and SHLA and combinations of binary and triple on to the expressions of MGMT, MLH1, MSH2, MSH6, PMS2 genes in TMZ resistance pathway was determined by RT-PCR. Genomic DNA damage effect of molecules was determined by COMET and cell cycle effects was determined by flow cytometry. The effects of TMZ, leptin and SHLA on the expression of genes in the TMZ resistance pathway differ from each other. It determined that there were significant differences among cell lines in terms of the effects of genomic DNA damage and cell cycle. Data obtained show that TMZ, leptin, and SHLA contribute to chemotherapeutic resistance at different levels in each cell type, leptin especially increases MGMT expression and does not cause general changes in MMR genes. Our results suggest that leptin and SHLA alone can cause DNA damage and accumulation in the G1 phase, but these effects vary in the combination of leptin and SHLA according to cell types. Our results indicate that leptin and SHLA, alone and combined, may play a role in the chemotherapeutic resistance to TMZ, and these effects vary with cell type and gene-specific. This is the first study investigating the effects of leptin and SHLA on TMZ resistance.