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Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

Overview of attention for article published in BMC Cancer, August 2016
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Title
Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models
Published in
BMC Cancer, August 2016
DOI 10.1186/s12885-016-2712-4
Pubmed ID
Authors

I. A. Netland, H. E. Førde, L. Sleire, L. Leiss, M. A. Rahman, B. S. Skeie, C. H. Gjerde, P. Ø. Enger, D. Goplen

Abstract

Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts. To assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V staining experiments were used to observe growth and apoptosis. Furthermore, Akt phosphorylation (S473), a downstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of glioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth. We found that dactolisib in vitro shows excellent dose dependent anti-growth properties and increase in apoptosis. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream effect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or inhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and the liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and accumulation of saliva in the oral cavity. Taken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in glioma treatment in vitro, its utility in vivo is questionable due to toxicity.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 22 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 22 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 3 14%
Student > Master 2 9%
Student > Postgraduate 2 9%
Student > Ph. D. Student 2 9%
Student > Doctoral Student 2 9%
Other 7 32%
Unknown 4 18%
Readers by discipline Count As %
Medicine and Dentistry 5 23%
Biochemistry, Genetics and Molecular Biology 4 18%
Agricultural and Biological Sciences 3 14%
Pharmacology, Toxicology and Pharmaceutical Science 1 5%
Nursing and Health Professions 1 5%
Other 4 18%
Unknown 4 18%

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 21 August 2016.
All research outputs
#7,139,958
of 8,255,097 outputs
Outputs from BMC Cancer
#2,810
of 3,474 outputs
Outputs of similar age
#214,197
of 253,888 outputs
Outputs of similar age from BMC Cancer
#178
of 255 outputs
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