Sunitinib impedes brain tumor progression and reduces tumor‐induced neurodegeneration in the microenvironment

Abstract

Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients.

Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema

“…The cell viability assay was performed using 3(4,5 dimethylthiazol) - 2,5 diphenyltetra-zolium (MTT) assay according to [33] the cell viability was measured. 3000 cells/well were plated in 96 well - plates one hours prior to the drug treatment.…”

Tumor microenvironment in treatment of glioma

“…We found that sunitinib normalizes the aberrant tumor-derived vasculature, reduces tumor vessel pathologies, and alleviate tumor-induced neurodegeneration. Furthermore, when combined with temozolomide, sunitinib could amplify the effects of temozolomide on glioma cells, of which the researchers thought to be related with influences of sunitinib on the brain tumor microenvironment [ 31 ].…”

Cabazitaxel operates anti-metastatic and cytotoxic via apoptosis induction and stalls brain tumor angiogenesis

“…During recent years the applicability of drugs or small molecule inhibitors on glioma cells particularly on vascularization and the tumor-immune interaction has been becoming center of interest [4–6]. However, one obstacle in delivering therapeutics to tumors of the central nervous system is tumor-induced angiogenesis which challenges the blood-brain barrier and absorption rate (BBB) [4, 7–9].…”