DNA Damaging Drugs in the Treatment of Glioblastoma: HR, Apoptosis, Autophagy and Senescence

Abstract

Alkylating agents, notably temozolomide, are 1st line therapeutics for the treatment of glioma. These agents induce different DNA lesions. One of the DNA adducts is O6-methylguanine (O6MeG), which is a powerful cytotoxic lesion. The damage is repaired by the suicide enzyme alkyltransferase (MGMT), which is a very important defense mechanism and marker of alkylating drug resistance. We have studied in detail how apoptosis is induced following O6MeG in glioma cells. We have shown that O6MeG triggered cell death is executed via the death receptor and the mitochondrial damage pathway, involving DNA double-strand breaks (DSB). The major pathway of repairing O6MeG induced DSB is homologous recombination (HR). Therefore, players involved in DSB recognition and HR are potential targets for therapy, such as NBS-1, ATM, Rad51 and XRCC2. In glioma cells, the efficiency of O6MeG to trigger the p53 dependent death receptor pathway is higher than the p53 independent mitochondrial pathway, which explains why p53 wt glioma cells are more sensitive to temozolomide than p53 mutated cells. Interestingly, p53 wt glioma cells are more resistant than p53 mutant glioma cells to chloroethylating agents (CCNU, ACNU), which are also applied in glioma therapy. This indicates that p53 has a dual role: one is up-regulation of the death receptor thus sensitizing to methylating agents, the other is upregulation of DNA repair thus protecting against O6chloroethylguanine-induced apoptosis (and necrosis). Data will be shown providing evidence that O6MeG induces not only apoptosis, but also autophagy and senescence. The interrelationship of these endpoints will be discussed. Work was supported by DFG KA724 and Deutsche Krebshilfe.