Cilengitide response in ultra-low passage glioblastoma cell lines: relation to molecular markers

Mullins, Christina Susanne; Schubert, Julia; Schneider, Björn; Linnebacher, Michael; Classen, Carl Friedrich

doi:10.1007/s00432-013-1457-6

Cited by 4 publications

(2 citation statements)

References 23 publications

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“…5 Therefore, the concentration of temozolomide that was used in this study was set at 100 mmol/l, which was considered to be approximately similar to the plasma concentration found in human subjects. 6 Temozolomide (Sigma-Aldrich, St Louis, MO, USA) was dissolved in dimethyl sulphoxide (DMSO; Sigma-Aldrich), which was the vehicle. The U251 cells were treated with either 100 mmol/L temozolomide (TMZ group) or 100 mmol/L DMSO (vehicle control group) for the stated periods (see below).…”

Section: Experimental Designmentioning

confidence: 99%

Mechanism of temozolomide-induced antitumour effects on glioma cells

Shen

Zheng

2013

J Int Med Res

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Objective: To investigate the mechanisms of action of the tumoricidal effects of temozolomide against the human glioma cell line U251 in vitro, and to provide preclinical proof-of-concept studies of the effects of temozolomide-containing regimens. Methods: U251 cells were exposed to 100 mmol/l temozolomide. Morphological alterations were monitored by light microscopy. Cell viability was measured using the 3 -(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis and the rate of apoptosis were determined using flow cytometry and the number of acidic vesicular organelles stained with acridine orange were analysed by fluorescence microscopy. The scratch recovery test was used to measure cell migration. Results: U251 cells that were treated with temozolomide displayed morphological alterations indicative of a rounder shape and impaired cellular adhesion to the cell culture plate compared with control U251 cells. Temozolomide reduced cell viability as measured by the MTT assay, caused cell cycle arrest in the gap 2/mitosis phase, inhibited cell migration and promoted autophagy in U251 cells. Conclusion: Temozolomide induced autophagic, but not apoptotic processes, in U251 cells and thus reduced their viability and migration.

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Section: Experimental Designmentioning

confidence: 99%

Mechanism of temozolomide-induced antitumour effects on glioma cells

Shen

Zheng

2013

J Int Med Res

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“…12,13 Cell lines were maintained in DMEM/F12 medium (PAN, P04-41500; C 10% FCS (PAN, P40-47500), 2 mM L-glutamine (Sigma, G-7513), antibiotics) and incubated at 37 C in a humidified atmosphere of 5% CO 2 . Antibiotics and antifungal agents were provided by the pharmacy of the Rostock University Medical Center.…”

Section: Glioblastoma Cell Linesmentioning

confidence: 99%

Arginine deprivation by arginine deiminase ofStreptococcus pyogenescontrols primary glioblastoma growthin vitroandin vivo

Fiedler

Strauss

Hering

et al. 2015

Cancer Biology & Therapy

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Arginine auxotrophy constitutes a weak point of several tumors, among them glioblastoma multiforme (GBM). Hence, those tumors are supposed to be sensitive for arginine-depleting substances, such as arginine deiminase (ADI). Here we elucidated the sensitivity of patient-individual GBM cell lines toward Streptococcus pyogenes-derived ADI. To improve therapy, ADI was combined with currently established and pre-clinical cytostatic drugs. Additionally, effectiveness of local ADI therapy was determined in xenopatients. Half of the GBM cell lines tested responded well toward ADI monotherapy. In those cell lines, viability decreased significantly (up to 50 %). Responding cell lines were subjected to combination therapy experiments to test if any additive or even synergistic effects may be achieved. Such promising results were obtained in 2/3 cases. In cell lines HROG02, HROG05 and HROG10, ADI and Palomid 529 combinations were most effective yielding more than 70 % killing after 2 rounds of treatment. Comparable boosted antitumoral effects were observed after adding chloroquine to ADI (>60% killing). Apoptosis, as well as cell cycle dysregulation were found to play a minor role. In some, but clearly not all cases, (epi-) genetic silencing of arginine synthesis pathway genes (argininosuccinate synthetase 1 and argininosuccinate lyase) explained obtained results. In vivo, ADI as well as the combination of ADI and SAHA efficiently controlled HROG05 xenograft growth, whereas adding Palomid 529 to ADI did not further increase the strong antitumoral effect of ADI. The cumulative in vitro and in vivo results proved ADI as a very promising candidate therapeutic, especially for development of adjuvant GBM combination treatments.

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MGMT promoter methylation is not correlated with integrin expression in malignant gliomas: clarifying recent clinical trial results

et al. 2018

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Integrin alpha-v-beta-3 (αβ) is important for invasive tumor growth and angiogenesis in glioblastomas (GBM). However, recent clinical trials on inhibition of this integrin led to ambiguous results whether patients with methylated or unmethylated O-methylguanine methyltransferase (MGMT) promoter might profit from this kind of therapy. Therefore, we addressed the still unanswered question about a possible correlation between integrin αβ expression and MGMT promoter methylation in GBM. For this purpose, tumor samples from newly diagnosed and untreated GBM patients with methylated (n = 22) or unmethylated (n = 17) MGMT promoter were simultaneously analyzed for integrin αβ expression by an automated immunohistochemical staining platform. Interestingly, subsequent semi-quantitative analysis by a special imaging software did not show any difference in integrin expression between patients with methylated or unmethylated MGMT promoter status. Moreover, further analysis of the integrin subunits via ELISA from histologic sections revealed that there is no difference in integrin subunit expression between these patients. Hence, our results are important for designing future clinical trials with respect to treatment stratification, while it still has to be identified which other molecular factors determine differential responses to targeted anti-integrin αβ treatment.

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Cilengitide response in ultra-low passage glioblastoma cell lines: relation to molecular markers

Abstract: As suggested by this analysis, patients with MGMT promoter-methylated GBM may benefit from addition of CGT to the standard TMZ treatment, while patients with MGMT promoter-unmethylated GBM may better respond to CGT monotherapy.

Cited by 4 publications

References 23 publications

Mechanism of temozolomide-induced antitumour effects on glioma cells

Mechanism of temozolomide-induced antitumour effects on glioma cells

Arginine deprivation by arginine deiminase ofStreptococcus pyogenescontrols primary glioblastoma growthin vitroandin vivo

MGMT promoter methylation is not correlated with integrin expression in malignant gliomas: clarifying recent clinical trial results

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