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

Autor(es)

Castro-Gamero, Angel Mauricio ^{[1, 2]} ; Borges, Kleiton Silva ^[1] ; Moreno, Daniel Antunes ^[1] ; Suazo, Veridiana Kill ^[3] ; Fujinami, Mayara Missono ^[3] ; Gomes Queiroz, Rosane de Paula ^[3] ; de Oliveira, Harley Francisco ^[4] ; Carlotti, Jr., Carlos Gilberto ^[5] ; Scrideli, Carlos Alberto ^[3] ; Tone, Luiz Gonzaga ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Genet, Fac Med Ribeirao Preto, BR-14048900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Hosp Clin, Fac Med Ribeirao Preto, Pediat Lab, BR-14048900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Dept Pediat, Fac Med Ribeirao Preto, BR-14048900 Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Dept Internal Med, Fac Med Ribeirao Preto, BR-14048900 Ribeirao Preto, SP - Brazil

^[5] Univ Sao Paulo, Dept Anat & Surg, Fac Med Ribeirao Preto, BR-14048900 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INVESTIGATIONAL NEW DRUGS; v. 31, n. 4, p. 858-870, AUG 2013.
• Citações Web of Science: 15

Resumo

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. (AU)

• Processo FAPESP: 09/50118-2 - Investigacao de novos alvos terapeuticos envolvidos com a instabilidade genomica em glioblastoma.
• Beneficiário: Luiz Gonzaga Tone
• Modalidade de apoio: Auxílio à Pesquisa - Regular