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

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

Author Castro-Gamero, Angel Mauricio Google Scholar
Borges, Kleiton Silva Google Scholar
Moreno, Daniel Antunes Google Scholar
Suazo, Veridiana Kill Google Scholar
Fujinami, Mayara Missono Google Scholar
Gomes Queiroz, Rosane de Paula Google Scholar
Oliveira, Harley Francisco de Google Scholar
Carlotti, Carlos Gilberto Google Scholar
Scrideli, Carlos Alberto Google Scholar
Tone, Luiz Gonzaga Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Abstract 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-Delta Ex3 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.
Keywords Cdk1 gene
Drug combination
Glioblastoma
M4N
Temozolomide
Survivin gene
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundacao de Apoio ao Ensino, Pesquisa e Assistencia, Hospital das Clinicas, Faculdade de Medicina de Ribeirao Preto, Universidade de São Paulo
Grant number FAPESP: 2009/50118-2
Date 2013-08-01
Published in Investigational New Drugs. Dordrecht: Springer, v. 31, n. 4, p. 858-870, 2013.
ISSN 0167-6997 (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 858-870
Origin http://dx.doi.org/10.1007/s10637-012-9917-4
Access rights Closed access
Type Article
Web of Science ID WOS:000322333600006
URI http://repositorio.unifesp.br/handle/11600/36586

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