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01-06-2017 | Original Paper

Dual treatment with shikonin and temozolomide reduces glioblastoma tumor growth, migration and glial-to-mesenchymal transition

Authors: Diana Matias, Joana Balça-Silva, Luiz Gustavo Dubois, Bruno Pontes, Valéria Pereira Ferrer, Luciane Rosário, Anália do Carmo, Juliana Echevarria-Lima, Ana Bela Sarmento-Ribeiro, Maria Celeste Lopes, Vivaldo Moura-Neto

Published in: Cellular Oncology | Issue 3/2017

Abstract

Purpose

Glioblastomas (GBM) comprise 17% of all primary brain tumors. These tumors are extremely aggressive due to their infiltrative capacity and chemoresistance, with glial-to-mesenchymal transition (GMT) proteins playing a prominent role in tumor invasion. One compound that has recently been used to reduce the expression of these proteins is shikonin (SHK), a naphthoquinone with anti-tumor properties. Temozolomide (TMZ), the most commonly used chemotherapeutic agent in GBM treatment, has so far not been studied in combination with SHK. Here, we investigated the combined effects of these two drugs on the proliferation and motility of GBM-derived cells.

Methods

The cytotoxic and proliferative effects of SHK and TMZ on human GBM-derived cells were tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), Ki67 staining and BrdU incorporation assays. The migration capacities of these cells were evaluated using a scratch wound assay. The expression levels of β3 integrin, metalloproteinases (MMPs) and GMT-associated proteins were determined by Western blotting and immunocytochemistry.

Results

We found that GBM-derived cells treated with a combination of SHK and TMZ showed decreases in their proliferation and migration capacities. These decreases were followed by the suppression of GMT through a reduction of β3 integrin, MMP-2, MMP-9, Slug and vimentin expression via inactivation of PI3K/AKT signaling.

Conclusion

From our results we conclude that dual treatment with SHK and TMZ may constitute a powerful new tool for GBM treatment by reducing therapy resistance and tumor recurrence.

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Title: Dual treatment with shikonin and temozolomide reduces glioblastoma tumor growth, migration and glial-to-mesenchymal transition
Authors: Diana Matias
Joana Balça-Silva
Luiz Gustavo Dubois
Bruno Pontes
Valéria Pereira Ferrer
Luciane Rosário
Anália do Carmo
Juliana Echevarria-Lima
Ana Bela Sarmento-Ribeiro
Maria Celeste Lopes
Vivaldo Moura-Neto
Publication date: 01-06-2017
Publisher: Springer Netherlands
Published in: Cellular Oncology / Issue 3/2017
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-017-0320-1

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