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The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKC?-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 ?1- and ?2B-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 PKC?-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKC? 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 PKC?-dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.

SUBMITTER: Assad Kahn S

PROVIDER: S-EPMC5130115 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway.

Assad Kahn Suzana S Costa Silvia Lima SL Gholamin Sharareh S Nitta Ryan T RT Dubois Luiz Gustavo LG Fève Marie M Zeniou Maria M Coelho Paulo Lucas Cerqueira PL El-Habr Elias E Cadusseau Josette J Varlet Pascale P Mitra Siddhartha S SS Devaux Bertrand B Kilhoffer Marie-Claude MC Cheshier Samuel H SH Moura-Neto Vivaldo V Haiech Jacques J Junier Marie-Pierre MP Chneiweiss Hervé H

EMBO molecular medicine 20160502 5

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 differentia ...[more]

PMID: 27138566

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Project description:As the most frequent cause of cancer-related death worldwide, lung cancer is closely related to inflammation. The interaction between tumor cells and inflammatory cells promotes tumor development and metastasis. During tumor development, vascular endothelial cells form the most important barrier to prevent tumor cell migration to the blood and tissue. Increased vascular permeability provides favorable conditions for the migration of tumor cells, and endothelial tight junctions are an important component of the vascular barrier. Protein kinase C δ is involved in the occurrence of non-small cell lung cancer and regulates vascular permeability and tight junction protein expression. Src kinase was reported to play an important role in TNF-α-induced endothelial inflammation. Ophiopogon Saponin C1 is a new chemical compound isolated from Liriope muscari, but its pharmacological activities have not been fully elucidated. Therefore, we tested the protective effects of C1 on endothelial permeability in a model of TNF-α-induced endothelial inflammation by transendothelial electrical resistance and sodium fluorescein assays and verified these results in a nude mouse model of experimental pulmonary adenocarcinoma metastasis. We further elucidated the mechanism of C1, which was based on the PKCδ and Src proteins, by Western blotting. C1 can inhibit lung cancer in vivo, regulate the level of plasma inflammation in tumor-bearing mice, and protect the pulmonary vascular barrier against injury induced by cancer. It was investigated the expression and distribution of the TJ index protein ZO-1 in mouse vascular endothelium and HUVECs and found that C1 could inhibit the degradation and breakage of the ZO-1 protein. Related signaling experiments confirmed that C1 can inhibit TNF-α and activation of PKCδ and Src kinase. This study laid the foundation for further analysis of new drugs with clear mechanisms and independent intellectual property rights of traditional Chinese medicines.

Dataset Information

The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKC?-dependent inhibition of the AKT pathway.

Publications

The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway.

Similar Datasets

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