Dexamethasone alleviates tumor-associated brain damage and angiogenesis.
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.
Department of Neurosurgery, University Hospital of Erlangen, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Zheng
Z
Fan
Department of Neurosurgery, University Hospital of Erlangen, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Tina
T
Sehm
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Manfred
M
Rauh
Department of Neurosurgery, University Hospital of Erlangen, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Michael
M
Buchfelder
Department of Neurosurgery, University Hospital of Erlangen, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Ilker Y
IY
Eyupoglu
Department of Neurosurgery, University Hospital of Erlangen, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Bavaria, Germany.
Nicolai E
NE
Savaskan
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000893:Anti-Inflammatory Agents; D042461:Vascular Endothelial Growth Factor A; D003907:Dexamethasone