Abstract
Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc −; SLC7a11) and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G) resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage.
Highlights
Gliomas are one of the leading causes in brain tumor-related deaths in children and humans [1] [2]
We show that dexamethasone decreases tumor-induced neuronal damage and reduces glioma cell growth in a concentration-dependent manner
DEXA promotes xCT and VEGFA expression in gliomas Since DEXA is a standard medical agent for the treatment of brain tumor-associated cerebral edema, we investigated the regulation of two genes associated with cytotoxic and vasogenic edema [7] [27]
Summary
Gliomas are one of the leading causes in brain tumor-related deaths in children and humans [1] [2]. The most aggressive and frequent ones are malignant gliomas, i.e. high grade gliomas including malignant gliomas WHO grade III and glioblastomas, WHO grade IV These tumors have a very poor prognosis despite of state-of-the-art multimodal treatments, including surgical resection, irradiation and chemotherapy [3]. 70% of malignant brain tumor patients receive dexamethasone treatment while they undergo multimodal radio-chemotherapy and a significant decrease in deaths has been related to this treatment [14]. This drug has been routinely used for decades in the management of cerebral edema, its exact mechanism of action on the tumor microenvironment is not fully uncovered. Anti-edema effects of VEGF-targeted therapeutic approaches have been established in preclinical models and phase I-II studies [10] [21]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
