Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression

Abstract

Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitrosourea) is the most commonly used chemotherapeutic agent for gliomas. However, the usefulness of this agent is limited because tumor cell resistance to BCNU is frequently found in clinical brain tumor therapy. The O6-methylguanine-DNA methyltransferase protein (MGMT) reverses alkylation at the O6 position of guanine and we have reported the role of MGMT in the response of brain tumors to alkylating agents. However, the different mechanisms underlying the patterns related to MGMT remain unclear. To better understand the molecular mechanism by which BCNU exerts its effect in glioma cell lines according MGMT expression, we used microarray technology to interrogate 3800 known genes and determine the gene expression profiles altered by BCNU treatment. Our results showed that treatment with BCNU alters the expression of a diverse group of genes in a time-dependent manner. A subset of gene changes was found common in both glioma cell lines and other subset is specific of each cell line. After 24 h of BCNU treatment, up-regulation of transcription factors involved in the nucleation of both RNA polymerase II and III transcription initiation complexes was reported. Interestingly, BCNU promoted the expression of actin-dependent regulators of chromatin. Similar effects were found with higher BCNU doses in MGMT+ cell line showing a similar mechanism that in MGMT-deficient cell with standard doses. Our data suggest that human glioma cell lines treated with BCNU, independently of MGMT expression, show changes in the expression of cell cycle and survival-related genes interfering the transcription mechanisms and the chromatin regulation.

Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury

“…Despite the mildness of the TBI models, as illustrated by the behavioral studies, large numbers of gene expressions and molecular pathways were altered in whole hippocampus RNA samples. Unique CNS related pathways observed in physical-TBI, included the ‘BCNU Glioma MGMT 48hrs Down’, ‘BCNU Glioma NOMGMT 48 hrs Down’ and ‘IFN Beta Glioma Dn’ pathways, that were up regulated 14 days after injury, likely as a consequence of the activation of highly abundant glial cells within the injured brain region (Azevedo et al, 2009; Israelsson et al, 2009; Bandres et al, 2005; Saijo and Glass, 2011). Genes with strong expression in brain occurring in the pathway ‘Chesler Brain Neural High Genes’ were also up regulated (Chesler et al, 2005), while there is sparse literature relating to the functional role of this pathway in CNS disease, its regulation observed here will be due to the source of the hippocampal RNA used for array studies.…”

Magnetic Nanoparticles for Tumor Imaging and Therapy: A So-Called Theranostic System

“…toxins, siRNA) with superior efficiency and a repetitive reaction mechanism to supersede the potency barrier by eradicating tumor at exceedingly low bio-available drug concentrations at the target site. For instance, IC50 of the proposed gelonin against human glioma cells was shown to be 15 pmol (49), about 7 orders of magnitude lower than that of commonly used anti-glioma agent BCNU (130 µM) (50). …”

Direct DNA Methylation Profiling Using Methyl Binding Domain Proteins

“…Radiation and some forms of alkylating chemotherapy are employed in the treatment of GMB. Patients receiving radiotherapy alone have lower survival rate compared to patients who received radiotherapy plus temozolomide (TMZ);41 TMZ and BCNU (1,3-bis (2-chloroethyl)-1-mitrosurea) are methylating/alkylating agents widely used for treatment of GBM 42. Long-term survivors (those living for 3 to 5 years) are characterized with hypermethylation of the MGMT promoter;43 MGMT is a DNA repair enzyme that confers cancer cell resistance to guanine O6-alkylating agent-based chemotherapy.…”