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Published on: October 27, 2014
New Anti-Angiogenic Therapy for Glioblastoma With the Anti-Depressant Sertraline
Nobushige Tsuboi1,2, Yoshihiro Otani1, Atsuhito Uneda1
1Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Background And Aims:
Anti-angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti-angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti-angiogenic inhibitors and identify novel anti-angiogenic drugs with clinical applications.
Results:
The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti-tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti-angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood-brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA-Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non-VEGF-mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model.
Conclusion:
Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways led to anti-angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti-angiogenic therapy for glioblastoma with safe, low cost, and fast availability.
Insights
Glioma stem cells differentiate into endothelial cells, causing resistance to anti-angiogenic therapy. Combining axitinib with sertraline shows promise for glioblastoma treatment.
Area of Science:
- Oncology
- Cancer Biology
- Drug Discovery
Background:
- Anti-angiogenic therapies improve survival in some cancers but not glioblastoma.
- Resistance to anti-angiogenic therapy is linked to glioma stem-like cells differentiating into tumor-derived endothelial cells.
- Mechanisms of drug resistance in tumor-derived endothelial cells and novel anti-angiogenic drugs are needed.
Purpose of the Study:
- Investigate the differentiation of glioma stem-like cells into tumor-derived endothelial cells.
- Elucidate mechanisms of drug resistance in tumor-derived endothelial cells.
- Identify novel anti-angiogenic drugs for glioblastoma with clinical applications.
Main Methods:
- Mouse glioma stem-like cells (005) were differentiated into tumor-derived endothelial cells under hypoxic conditions.
- In vivo and in vitro studies evaluated the anti-tumor effects of novel anti-angiogenic drugs, including sertraline, using tube formation assays, RNA-Seq, immunohistochemistry, and MRI.
- Drug repositioning strategies were employed using existing blood-brain barrier permeable drugs.
Main Results:
- Tumor-derived endothelial cells exhibited endothelial characteristics independent of the vascular endothelial growth factor (VEGF) pathway.
- VEGF pathway inhibition did not improve anti-tumor effects and increased tumor-derived endothelial cell percentage in the 005 mouse model.
- Sertraline inhibited tube formation, reduced Lama4 and Ang2 expressions in tumor-derived endothelial cells, and, when combined with axitinib, improved survival and reduced tumor growth in the 005 mouse model.
Conclusions:
- Tumor vascular endothelial cell diversity contributes to anti-angiogenic therapy resistance.
- The combination of axitinib and sertraline offers a potentially effective, safe, low-cost, and readily available anti-angiogenic therapy for glioblastoma.
