Astrocytomas are the most common primary brain tumors. They are very resistant to therapies and usually progress rapidly to high-grade lesions. Here, we investigated the potential role of DNA repair genes in astrocytoma progression and resistance. To this aim, we performed a polymerase chain reaction array-based analysis focused on DNA repair genes and searched for correlations between expression patters and survival prognoses. We found 19 genes significantly altered. Combining these genes in all possible arrangements, we found 421 expression signatures strongly associated with poor survival. Importantly, five genes (DDB2, EXO1, NEIL3, BRCA2, and BRIP1) were independently correlated with worse prognoses, revealing single-gene signatures. Moreover, silencing of EXO1, which is remarkably overexpressed, promoted faster restoration of double-strand breaks, while NEIL3 knockdown, also highly overexpressed, caused an increment in DNA damage and cell death after irradiation of glioblastoma cells. These results disclose the importance of DNA repair pathways for the maintenance of genomic stability of high-grade astrocytomas and suggest that EXO1 and NEIL3 overexpression confers more efficiency for double-strand break repair and resistance to reactive oxygen species, respectively. Thereby, we highlight these two genes as potentially related with tumor aggressiveness and promising candidates as novel therapeutic targets.
Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, showing rapid development and resistance to therapies. On average, patients survive 14.6 months after diagnosis and less than 5% survive five years or more. Several pieces of evidence have suggested that the DNA damage signaling and repair activities are directly correlated with GBM phenotype and exhibit opposite functions in cancer establishment and progression. The functions of these pathways appear to present a dual role in tumorigenesis and cancer progression. Activation and/or overexpression of ATRX, ATM and RAD51 genes were extensively characterized as barriers for GBM initiation, but paradoxically the exacerbated activity of these genes was further associated with cancer progression to more aggressive stages. Excessive amounts of other DNA repair proteins, namely HJURP, EXO1, NEIL3, BRCA2, and BRIP, have also been connected to proliferative competence, resistance and poor prognosis. This scenario suggests that these networks help tumor cells to manage replicative stress and treatment-induced damage, diminishing genome instability and conferring therapy resistance. Finally, in this review we address promising new drugs and therapeutic approaches with potential to improve patient survival. However, despite all technological advances, the prognosis is still dismal and further research is needed to dissect such complex mechanisms.
It is well known that phytotherapy has grown in popularity in recent years. Because a drug cannot be administered without ensuring its effectiveness and safety, the standardization and regulation of phytotherapeutic drugs are required by the global market and governmental authorities. This article describes a simple and reliable high-performance liquid chromatography-diode array detection analysis method for the simultaneous detection of myricetin-3-O-b-Dgalactopyranoside, myricetin-3-O-a-L-arabinopyranoside, and myricetin-3-O-a-L-rhaminopyranoside present in the hydroethanolic extract (ethanol/H2O, 7:3, v/v) of Pouteria torta. The mutagenic activity of the extract was evaluated on Salmonella typhimurium and by an in vivo micronucleus test on the peripheral blood cells of Swiss mice. The linearity, sensitivity, selectivity, repeatability, accuracy, and precision of the assay were evaluated. The analytical curves were linear and exhibited good repeatability (with a deviation of less than 5%) and demonstrated good recovery (within the 83-107% range). The results demonstrate that the hydroethanolic extract exhibited a mutagenic activity in both assays, suggesting caution in the use of this plant in folk medicine.
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