The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKC δ‐dependent inhibition of the AKT pathway

Abstract

A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor‐initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1‐ and α2B‐adrenergic receptor antagonist, as the most potent inducer of patient‐derived glioblastoma‐initiating cell death. Prazosin triggered apoptosis of glioblastoma‐initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient‐derived glioblastoma‐initiating cells, and increased survival of glioblastoma‐bearing mice. We found that prazosin acted in glioblastoma‐initiating cells independently from adrenergic receptors. Its off‐target activity occurred via a PKCδ‐dependent inhibition of the AKT pathway, which resulted in caspase‐3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin‐treated glioblastoma‐initiating cells, as well as prazosin‐induced apoptosis. Based on these data, we conclude that prazosin, an FDA‐approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ‐dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.

A Novel Theranostic Strategy for MMP-14–Expressing Glioblastomas Impacts Survival

“…We defined GICs (Supplementary Fig. 2) by a combination of established cell surface markers, CD133, CD15 and CD49F (38,39). Considering the heterogeneity of tumors, we confirmed the reliability of these markers in identifying GICs in pcGBM39 and pcGBM2 (Supplementary Fig.…”

Patient-derived osteosarcoma cells are resistant to methotrexate

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“…Immunocytochemistry analysis was performed as previously described[ 15 ]. Briefly, cells were fixed with 4% paraformaldehyde (PFA) in PBS for 15min, washed with PBS and incubated with 5%BSA for 30min.…”

Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness

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