Cellular and molecular portrait of eleven human glioblastoma cell lines irradiated with photons or carbon ions

The multiform glioblastoma (GBM) is a heterogeneous and highly invasive entity, making it the most aggressive brain tumor. The standard-of-care for glioblastoma consists of surgical resection, radiotherapy and chemotherapy, but despite the recent improvement of therapeutic protocols, the recurrence seems inevitable. Due to a better dose localization in the tumor volume and a greater Relative Biological Efficiency (RBE), carbon ion therapy seems to be a promising alternative to conventional radiotherapy. However, to optimize individual treatment by hadrontherapy the exact carbon equivalent dose needs to be determined from data obtained after photon irradiation. Therefore, molecular and cellular investigations of GBM are required in order to improve the prediction and treatment of brain tumors. In this study, we have examined the radiobiological features of 11 human glioma cell lines displaying gradual radiosensitivity, following photon- or carbon-therapy in order to optimize and secure antiglioma strategies. Independent of p53 or O6-methylguanine-DNA methyltransferase (MGMT) status, all cell lines respond to both types of radiation by a G2/M phase arrest followed by the appearance of mitotic catastrophe, which is concluded by a ceramide-dependent-apoptotic cell death. Statistical analyses demonstrate that: (i) the surviving fraction at 2Gy (SF2) and the dose for 10% survival (D10) photon values are correlated with that obtained in response to carbon ions; (ii) regardless of p53, MGMT status, and radiosensitivity, the release of ceramide is associated with the induction of late apoptosis; (iii) the appearance of polyploid cells after photon irradiation could predict the RBE to carbon ions. The present study clearly provides a consistent database of the cellular and molecular response of glioblastoma cell lines to photon irradiation, and to the best of our knowledge represents the largest archive for carbon ion hadrontherapy response of glioblastoma cells. This type of archive is intended to customize the treatment of patients by allowing the development of new predictive mathematical models for the response of tumors to radiation, and ultimately could improve hadrontherapy treatment plans.