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01-04-2019 | PRECLINICAL STUDIES

Euphol, a tetracyclic triterpene, from Euphorbia tirucalli induces autophagy and sensitizes temozolomide cytotoxicity on glioblastoma cells

Authors: Viviane A. O. Silva, Marcela N. Rosa, Vera Miranda-Gonçalves, Angela M. Costa, Aline Tansini, Adriane F. Evangelista, Olga Martinho, Adriana C. Carloni, Chris Jones, João Paulo Lima, Luiz F. Pianowski, Rui Manuel Reis

Published in: Investigational New Drugs | Issue 2/2019

Summary

Glioblastoma (GBM) is the most frequent and aggressive type of brain tumor. There are limited therapeutic options for GBM so that new and effective agents are urgently needed. Euphol is a tetracyclic triterpene alcohol, and it is the main constituent of the sap of the medicinal plant Euphorbia tirucalli. We previously identified anti-cancer activity in euphol based on the cytotoxicity screening of 73 human cancer cells. We now expand the toxicological screening of the inhibitory effect and bioactivity of euphol using two additional glioma primary cultures. Euphol exposure showed similar cytotoxicity against primary glioma cultures compared to commercial glioma cells. Euphol has concentration-dependent cytotoxic effects on cancer cell lines, with more than a five-fold difference in the IC₅₀ values in some cell lines. Euphol treatment had a higher selective cytotoxicity index (0.64–3.36) than temozolomide (0.11–1.13) and reduced both proliferation and cell motility. However, no effect was found on cell cycle distribution, invasion and colony formation. Importantly, the expression of the autophagy-associated protein LC3-II and acidic vesicular organelle formation were markedly increased, with Bafilomycin A1 potentiating cytotoxicity. Finally, euphol also exhibited antitumoral and antiangiogenic activity in vivo, using the chicken chorioallantoic membrane assay, with synergistic temozolomide interactions in most cell lines. In conclusion, euphol exerted in vitro and in vivo cytotoxicity against glioma cells, through several cancer pathways, including the activation of autophagy-associated cell death. These findings provide experimental support for further development of euphol as a novel therapeutic agent for GBM, either alone or in combination chemotherapy.

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Title: Euphol, a tetracyclic triterpene, from Euphorbia tirucalli induces autophagy and sensitizes temozolomide cytotoxicity on glioblastoma cells
Authors: Viviane A. O. Silva
Marcela N. Rosa
Vera Miranda-Gonçalves
Angela M. Costa
Aline Tansini
Adriane F. Evangelista
Olga Martinho
Adriana C. Carloni
Chris Jones
João Paulo Lima
Luiz F. Pianowski
Rui Manuel Reis
Publication date: 01-04-2019
Publisher: Springer US
Published in: Investigational New Drugs / Issue 2/2019
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-018-0620-y

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