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Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination

Overview of attention for article published in Journal of Experimental & Clinical Cancer Research, September 2017
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Title
Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination
Published in
Journal of Experimental & Clinical Cancer Research, September 2017
DOI 10.1186/s13046-017-0588-z
Pubmed ID
Authors

Xin Zhang, Ran Xu, Chao Zhang, Yangyang Xu, Mingzhi Han, Bin Huang, Anjing Chen, Chen Qiu, Frits Thorsen, Lars Prestegarden, Rolf Bjerkvig, Jian Wang, Xingang Li

Abstract

Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo. U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 μM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models. This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 20 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 20 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 3 15%
Other 2 10%
Student > Doctoral Student 2 10%
Student > Postgraduate 2 10%
Professor 2 10%
Other 4 20%
Unknown 5 25%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 5 25%
Agricultural and Biological Sciences 3 15%
Neuroscience 2 10%
Medicine and Dentistry 2 10%
Unspecified 1 5%
Other 1 5%
Unknown 6 30%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 September 2017.
All research outputs
#9,365,511
of 11,717,557 outputs
Outputs from Journal of Experimental & Clinical Cancer Research
#340
of 646 outputs
Outputs of similar age
#193,232
of 263,737 outputs
Outputs of similar age from Journal of Experimental & Clinical Cancer Research
#8
of 12 outputs
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So far Altmetric has tracked 646 research outputs from this source. They receive a mean Attention Score of 2.5. This one is in the 30th percentile – i.e., 30% of its peers scored the same or lower than it.
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We're also able to compare this research output to 12 others from the same source and published within six weeks on either side of this one. This one is in the 25th percentile – i.e., 25% of its contemporaries scored the same or lower than it.