Exploring the role of ferroptosis in temozolomide death induction in glioblastoma

Abstract

Glioblastoma is an extremely aggressive type of cancer and patients with this type of tumor have an average survival of 12 to 15 months. Almost all patients succumb in the first years after diagnosis of the disease due to resistance to chemotherapy. Standard chemotherapy is performed by administering temozolomide (TMZ) which is an alkylating agent that induces cell death by inducing various DNA damage. Among the different types of injuries caused by TMZ O6-methylguanine is the most toxic. This lesion is repaired by the enzyme O6-methylguanine methyltransferase (MGMT) and failure to repair this lesion can lead to cell death via mismatch repair pathway activity (MMR). As a consequence, MGMT expression and MMR activity are strongly associated with TMZ resistance. However, due to the high recurrence after TMZ treatment even in patients who have no changes in these pathways, other cellular processes may be involved in TMZ resistance. In this sense, our group demonstrated that the transcription factor NRF2 can mediate resistance to TMZ through induction of synthesis and utilization of glutathione. It has recently been described that NRF2 modulates a type of cell death called ferroptosis and that this function of NRF2 is closely linked to glutathione metabolism. Therefore, in this master's project we will evaluate if TMZ treatment is capable of inducing ferroptosis and if this process is regulated by NRF2. Importantly, there are already regulators of ferroptosis in use in the clinic, for example sorafenib, for the treatment of kidney, liver and thyroid cancer. Thus, we intend to establish in vitro treatment protocol using the combination TMZ and ferroptosis modulators in human glioblastoma cells. (AU)