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01-08-2013 | PRECLINICAL STUDIES

Tetra-O-methyl nordihydroguaiaretic acid, an inhibitor of Sp1-mediated survivin transcription, induces apoptosis and acts synergistically with chemo-radiotherapy in glioblastoma cells

Authors: Angel Mauricio Castro-Gamero, Kleiton Silva Borges, Daniel Antunes Moreno, Veridiana Kill Suazo, Mayara Missono Fujinami, Rosane de Paula Gomes Queiroz, Harley Francisco de Oliveira, Carlos Gilberto Carlotti Jr., Carlos Alberto Scrideli, Luiz Gonzaga Tone

Published in: Investigational New Drugs | Issue 4/2013

Summary

Glioblastoma (GBM), one of the most malignant human neoplasias, responds poorly to current treatment modalities, with temozolomide (TMZ) being the drug most frequently used for its treatment. Tetra-O-methyl Nordihydroguaiaretic Acid (M4N) is a global transcriptional repressor of genes dependent on the Sp1 transcription factor, such as Survivin and Cdk1. In the present study we evaluated the gene expression of Survivin, its spliced variants and Cdk1 in GBM samples and cell lines. Moreover, we investigated the effects of M4N combined or not with TMZ and/or radiation on GBM primary cultures and cell lines. qRT-PCR assays were performed to determine the Survivin-spliced variants and Cdk1 gene mRNA expression in GBM tumor samples and cell lines. Cell proliferation was measured by XTT assay and cell cycle and apoptosis were determined by flow cytometry. Drug combination analyses using different schedules of administration (simultaneous and sequential) were performed on GBM cell lines and primary cultures based on the Chou-Talalay method. For clonogenic survival, doses of 2, 4, and 6 Gy of gamma radiation. were used. All Survivin-spliced variants and the Cdk1 gene were expressed in GBM samples (n = 16) and cell lines (n = 6), except the Survivin-2B variant that was only expressed in GBM cell lines. M4N treatment down regulated the expression of Cdk1, Survivin and the Survivin-ΔEx3 variant, while the Survivin-2B variant was up-regulated. M4N decreased the cell proliferation separately and synergistically with TMZ, and enhanced the effects of radiation, mainly when associated with TMZ. M4N also induced apoptotic cell death, decreased the mitotic index and arrested the cell cycle mainly in the G2/M phase. Our results suggest a potential clinical application of M4N in combination with TMZ and radiation for GB treatment.

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Title: Tetra-O-methyl nordihydroguaiaretic acid, an inhibitor of Sp1-mediated survivin transcription, induces apoptosis and acts synergistically with chemo-radiotherapy in glioblastoma cells
Authors: Angel Mauricio Castro-Gamero
Kleiton Silva Borges
Daniel Antunes Moreno
Veridiana Kill Suazo
Mayara Missono Fujinami
Rosane de Paula Gomes Queiroz
Harley Francisco de Oliveira
Carlos Gilberto Carlotti Jr.
Carlos Alberto Scrideli
Luiz Gonzaga Tone
Publication date: 01-08-2013
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-012-9917-4

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