Effects of tetra-O-methyl nordihydroguaiaretic acid in glioblastoma: a combined transcriptomic and proteomic study

Abstract

Glioblastoma is one of the most aggressive human cancers. Despite current advances in multimodality therapies, such as surgery, radiotherapy and chemotherapy, the outcome for patients with this neoplasia remains fatal. Thus, novel effective treatment regimens are urgently needed.Tetra-O-methyl nordihydroguaiaretic acid (M4N), a global transcription inhibitor of Sp1-regulated genes, has shown anticancer effects in diverse tumor models, as well as significant levels of safety and tolerability in gliomas patients. Moreover, pre-clinical studies developed by our research group have corroborated their antineoplastic effects and have demonstrated their synergistic effects when combined with temozolomide and radiation in cell lines and primary cultures of glioblastoma from samples of patients diagnosed in Hospital das Clínicas de Ribeirão Preto (USP). These results were associated with down-regulation of both Sp1-regulated BIRC5 and CDK1 genes. However, none study has described the global molecular consequences that occur after M4N treatment in these cells. The proposal of this project is, from a transcript- and proteomic view point, to study the changes in large scale of both mRNA and protein levels caused by M4N treatment in glioblastoma cell lines; moreover, will be investigated the oncogenic pathways involved in the synergistic effects of M4N in combination with radiation and temozolomide. Additionally, validation of cell parameters as proliferation, clonogenic capacity and both gene and proteic expression by qRT-PCR and western blot will be performed to complement the investigation. (AU)