Ionizing radiation causes oxidative stress, leading to acute and late cellular responses. We previously demonstrated that irradiation of non-proliferating endothelial cells, as observed in normal tissues, induces early apoptosis, which can be inhibited by pretreatment with Sphingosine-1-Phosphate. We now propose to better characterize the long-term radiation response of endothelial cells by studying the molecular pathways associated with senescence and its link with acute apoptosis. First, senescence was validated in irradiated quiescent microvascular HMVEC-L in a dose- and time-dependent manner by SA β-galactosidase staining, p16 and p21 expression, pro-inflammatory IL-8 secretion and DNA damage response activation. This premature aging was induced independently of Sphingosine 1-Phosphate treatment, supporting its non-connection with acute IR-induced apoptosis. Then, senescence under these conditions showed persistent activation of p53 pathway and mitochondrial dysfunctions, characterized by O2·- generation, inhibition of respiratory complex II activity and over-expression of SOD2 and GPX1 detoxification enzymes. Senescence was significantly inhibited by treatment with pifithrin-α, a p53 inhibitor, or by MnTBAP, a superoxide dismutase mimetic, validating those molecular actors in IR-induced endothelial cell aging. However, MnTBAP, but not pifithrin-α, was able to limit superoxide generation and to rescue the respiratory complex II activity. Furthermore, MnTBAP was not modulating p53 up-regulation, suggesting that IR-induced senescence in quiescent endothelial cells is provided by at least 2 different pathways dependent of the mitochondrial oxidative stress response and the p53 activation. Further characterization of the actors involved in the respiratory complex II dysfunction will open new pharmacological strategies to modulate late radiation toxicity.
Glioblastoma is the most common primary brain malignancy and carries with it a poor prognosis. New agents are urgently needed, however nearly all Phase III trials of GBM patients of the past 25 years have failed to demonstrate improvement in outcomes. In 2019, the National Cancer Institute Clinical Trials and Translational Research Advisory Committee (CTAC) Glioblastoma Working Group (GBM WG) identified 5 broad areas of research thought to be important in the development of new herapeutics for GBM. Among those was optimizing radioresponse for GBM in situ. One such strategy to increase radiation efficacy is the addition of a radiosensitizer to improve the therapeutic ratio by enhancing tumor sensitivity while ideally having minimal to no effect on normal tissue. Historically the majority of trials using radiosensitizers have been unsuccessful, but they provide important guidance in what is required to develop agents more efficiently. Improved target selection is essential for a drug to provide maximal benefit, and once that target is identified it must be validated through pre-clinical studies. Careful selection of appropriate in vitro and in vivo models to demonstrate increased radiosensitivity and suitable bioavailability are then necessary to prove that a drug warrants advancement to clinical investigation. Once investigational agents are validated pre-clinically, patient trials require consistency both in terms of planning study design as well as reporting efficacy and toxicity in order to assess the potential benefit of the drug. Through this paper we hope to outline strategies for developing effective radiosensitizers against GBM using as models the examples of XPO1 inhibitors and HDAC inhibitors developed from our own lab.
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