Lipid Peroxidation Plays an Important Role in Chemotherapeutic Effects of Temozolomide and the Development of Therapy Resistance in Human Glioblastoma.
2020; 13 (3): 100748
Glioblastoma (GBM) is the most malignant primary brain tumor. Relapse occurs regularly, and the clinical behavior seems to be due to a therapy-resistant subpopulation of glioma-initiating cells that belong to the group of cancer stem cells. Aldehyde dehydrogenase (ALDH) has been identified as a marker for this cell population, and we have shown previously that ALDH1A3-positive GBM cells are more resistant against temozolomide (TMZ) treatment. However, it is still unclear how ALDH expression mediates chemoresistance.ALDH1A3 expression was analyzed in 112 specimens from primary and secondary surgical resections of 56 patients with GBM (WHO grade IV). All patients received combined adjuvant radiochemotherapy. For experimental analysis, CRISPR-Cas9-induced knockout cells from three established GBM cell lines (LN229, U87MG, T98G) and two glioma stem-like cell lines were investigated after TMZ treatment.ALDH1A3 knockout cells were more sensitive to TMZ, and oxidative stress seemed to be the molecular process where ALDH1A3 exerts its role in resistance against TMZ. Oxidative stress led to lipid peroxidation, yielding active aldehydes that were detoxified by ALDH enzymatic activity. During the metabolic process, autophagy was induced leading to downregulation of the enzyme, but ALDH1A3 is upregulated to even higher expression levels after finishing the TMZ therapy in vitro. Recurrent GBMs show significantly higher ALDH1A3 expression than the respective samples from the primary tumor, and patients suffering from GBM with high ALDH1A3 expression showed a shorter median survival time (12 months vs 21 months, P < .05).Oxidative stress is an important and clinically relevant component of TMZ-induced therapeutic effects. Cytotoxicity seems to be mediated by aldehydes resulting from lipid peroxidation, and ALDH1A3 is able to reduce the number of toxic aldehydes. Therefore, we present a molecular explanation of the role of ALDH1A3 in therapeutic resistance of human GBM cells.
View details for DOI 10.1016/j.tranon.2020.100748
View details for PubMedID 32087559
View details for PubMedCentralID PMC7033364
Identification of psychiatric disorder subtypes from functional connectivity patterns in resting-state electroencephalography.
Nature Biomedical Engineering
View details for DOI 10.1038/s41551-020-00614-8
Correlation of the quantitative level of MGMT promoter methylation and overall survival in primary diagnosed glioblastomas using the quantitative MethyQESD method.
Journal of clinical pathology
O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation is a high predictive factor for therapy results of temozolomide in patients with glioma. The objective of this work was to analyse the impact of MGMT promoter methylation in patients with primary diagnosed glioblastoma (GBM) relating to survival using a quantitative method (methylation quantification of endonuclease-resistant DNA, MethyQESD) by verifying a cut-off point for MGMT methylation provided by the literature (≥10%) and calculating an optimal cut-off.67 patients aged 70 years or younger, operated between January 2013 and December 2015, with newly diagnosed IDH wild-type GBM and clinical follow-up were retrospectively investigated in this study. A known MGMT promoter methylation status was the inclusion criteria.Median overall survival (OS) was 16.9 months. Patients who had a methylated MGMT promoter region of ≥10% had an improved OS compared with patients with a methylated promoter region of <10% (p=0.002). Optimal cut-off point for MGMT promoter methylation was 11.7% (p=0.012).The results confirm that the quantitative level of MGMT promoter methylation is a positive prognostic factor in newly diagnosed patients with GBM. The cut-off provided by the literature (≥10%) and the calculated optimal cut-off value of 11.7% give a statistically significant separation. Hence, MethyQESD is a reliable method to calculate MGMT promoter methylation in GBM.
View details for DOI 10.1136/jclinpath-2019-206104
View details for PubMedID 31422371
Theranostic nanoparticles enhance the response of glioblastomas to radiation
2019; 3(4) (299-310)
View details for DOI 10.7150/ntno.35342
Aldehyde dehydrogenase 1A3 (ALDH1A3) is regulated by autophagy in human glioblastoma cells
2018; 417: 112–23
Aldehyde dehydrogenase is a polymorphic enzyme, which responsible for the oxidation of aldehydes. It has been shown that ALDH1A3 is expressed in human glioblastomas and that its expression correlates with a worse prognosis. In our present study ALDH1A3 expression was associated with resistance against Temozolomide (TMZ) treatment and sensitivity could be re-established in ALDH1A3 knockout cells. TMZ treatment at high concentrations diminished ALDH1A3 protein and this downregulation made the tumor cells more sensitive to chemotherapy. ALDH1A3 was post-transcriptionally regulated since mRNA levels were not affected by TMZ treatment. With increasing concentrations of TMZ, autophagy was up-regulated, and we found evidence for a physical interaction between ALDH1A3 and p62, an important adaptor protein in autophagosomes indicating that ALDH1A3 protein was downregulated by autophagy. So far, the results of the exact role of autophagy in tumor development and tumor growth are inconsistent. Our data indicate that ALDH1A3, that is directly involved in therapy resistance of glioblastoma, is regulated by autophagy during chemotherapy.
View details for DOI 10.1016/j.canlet.2017.12.036
View details for Web of Science ID 000425071000011
View details for PubMedID 29306018
Temozolomide induces autophagy in primary and established glioblastoma cells in an EGFR independent manner
2017; 14 (1): 322–28
Despite major contributions to the current molecular understanding of autophagy, a recycling process for intracellular components to maintain homeostatic balance, relatively little is known about the interacting networks. To address this issue, the current study investigated the role of autophagy in primary and established glioblastoma multiforme (GBM) cells and its interplay with the epidermal growth factor receptor (EGFR) and the standard chemotherapeutic agent temozolomide (TMZ). TMZ treatment leads to an upregulation of autophagy, predominantly in primary GBM cells. The interaction between EGFR and Beclin-1, an important protein in initiating autophagy, was assessed using a cancer cell line transfected with EGFRvIII, and by stimulation with EGF. The results of the current study suggest that Beclin-1 and EGFR do not interact directly in either primary or established GBM cells. To enable the limited efficacy of patient treatment strategies of GBM to potentially be enhanced through the application of autophagy regulators, the multiple cellular interactions of autophagy require further elucidation.
View details for DOI 10.3892/ol.2017.6107
View details for Web of Science ID 000405645700045
View details for PubMedID 28693171
View details for PubMedCentralID PMC5494811
Test-retest reliability of transcranial magnetic stimulation EEG evoked potentials
Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (TMS-EEG), offer a powerful tool for measuring causal interactions in the human brain. However, the test-retest reliability of TEPs, critical to their use in clinical biomarker and interventional studies, remains poorly understood.We quantified TEP reliability to: (i) determine the minimal TEP amplitude change which significantly exceeds that associated with simply re-testing, (ii) locate the most reliable scalp regions of interest (ROIs) and TEP peaks, and (iii) determine the minimal number of TEP pulses for achieving reliability.TEPs resulting from stimulation of the left dorsolateral prefrontal cortex were collected on two separate days in sixteen healthy participants. TEP peak amplitudes were compared between alternating trials, split-halves of the same run, two runs five minutes apart and two runs on separate days. Reliability was quantified using concordance correlation coefficient (CCC) and smallest detectable change (SDC).Substantial concordance was achieved in prefrontal electrodes at 40 and 60 ms, centroparietal and left parietal ROIs at 100 ms, and central electrodes at 200 ms. Minimum SDC was found in the same regions and peaks, particularly for the peaks at 100 and 200 ms. CCC, but not SDC, reached optimal values by 60-100 pulses per run with saturation beyond this number, while SDC continued to improve with increased pulse numbers.TEPs were robust and reliable, requiring a relatively small number of trials to achieve stability, and are thus well suited as outcomes in clinical biomarker or interventional studies.
View details for DOI 10.1016/j.brs.2017.12.010
Deguelin-induced blockade of PI3K/protein kinase B/MAP kinase signaling in zebrafish and breast cancer cell lines is mediated by down-regulation of fibroblast growth factor receptor 4 activity
PHARMACOLOGY RESEARCH & PERSPECTIVES
2016; 4 (2): e00212
Deguelin, a natural component derived from leguminous plants, has been used as pesticide in some regions. Accumulating evidence show that deguelin has promising chemopreventive and therapeutic activities against cancer cells. This study shows that low concentrations of deguelin can lead to significant delay in zebrafish embryonic development through growth inhibition and induction of apoptosis. Furthermore, we identified fibroblast growth factor receptor 4 (FGFR4) as the putative target of deguelin. The candidate was initially identified by a microarray approach and then validated through in vitro experiments using hormone-responsive (MCF-7) and nonresponsive (MDA-MB-231) human breast cancer cell lines. The results show that deguelin suppressed cell proliferation and induced apoptosis in both cancer cell lines, but not in Hs 578Bst cells, by blocking PI3K/AKT and mitogen-activated protein kinases (MAPK) signaling. The FGFR4 mRNA and protein level also diminished in a dose-dependent manner. Interestingly, we found that forced FGFR4 overexpression attenuated deguelin-induced proliferative suppression and apoptotic cell death in both zebrafish and MCF-7 cell lines, p-AKT and p-ERK levels were restored upon FGFR4 overexpression. Taken together, our results strongly suggest that deguelin inhibition of PI3K/AKT and MAPK signaling in zebrafish and breast cancer cell lines is partially mediated through down-regulation of FGFR4 activity.
View details for DOI 10.1002/prp2.212
View details for Web of Science ID 000410351700014
View details for PubMedID 27069628
View details for PubMedCentralID PMC4804323