Glucose Influences the Response of Glioblastoma Cells to Temozolomide and Dexamethasone.

OBJECTIVE: Current research indicates that weakness of glucose metabolism plays an important role in silencing of invasiveness and growth of hypoxic tumors such as GBM. Moreover, there are indications that DXM, frequently used in treatment, may support GBM energy metabolism and provoke its recurrence. METHODS: We carried out in vitro experiments on the commercial T98G cell line and two primary GBM lines (HROG02, HROG17) treated with TMZ and/or DXM in physiological oxygen conditions for GBM (2.5% oxygen) and for comparison, in standard laboratory conditions (20% oxygen). The influence of different glucose levels on selected malignancy features of GBM cells-cellular viability and division, dynamic of cell culture changes, colony formation and concentration of InsR have been elevated. RESULTS: Under 2.5% oxygen and high glucose concentration, an attenuated cytotoxic effect of TMZ and intensification of malignancy features in all glioblastoma cell lines exposed to DXM was seen. Furthermore, preliminary retrospective analysis to assess the correlation between serum glucose levels and Ki-67 expression in surgical specimens derived from patients with GBM (IV) treated with radio-chemotherapy and prophylactic DXM therapy was performed. CONCLUSION: The data suggest a link between the in vitro study results and clinical data. High glucose can influence on GBM progression through the promotion of the following parameters: cell viability, dispersal, InsR expression and cell proliferation (Ki-67). However, this problem needs more studies and explain the mechanism of action studied drugs.

Tricyclic Antidepressants Modulate Stressed Mitochondria in Glioblastoma Multiforme Cells.

A common feature of solid tumors, including glioblastoma multiforme (GBM), is mitochondrial dysfunction. However, it is reported that the current standard of anti-GBM therapies may potentiate mitochondrial damage and, in effect, support the aggressive character of cancer. As mitochondria are implicated in the modulation of cellular drug sensitivity and chemoresistance mechanisms, activation-stressed mitochondria in GBM cells may represent a new target for anti-GBM therapy that is nontoxic for normal cells. METHODS: As mitochondria are possible targets for antidepressant drugs used as adjuvant therapy in patients with GBM, we examined their influence on mitochondrial volume and activity, reactive oxygen species level, extracellular lactate concentration, and p65 NF-κB gene expression in GBM cells. RESULTS: Our investigation showed, for the first time, that tricyclic antidepressants, imipramine and amitriptyline, partially reverse GBM abnormalities. CONCLUSION: In the light of reported studies, the mitochondrial disturbance observed in glioma cells is a dynamic process that can be reversed or silenced. Moreover, imipramine and amitriptyline are attractive cellular metabolic modulators and can potentially be used to restoring a proper function of mitochondria in GBM cells.

Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme.

PURPOSE: The role of glioma stem cells (GSCs) in cancer progression is currently debated; however, it is hypothesised that this subpopulation is partially responsible for therapeutic resistance observed in glioblastoma multiforme (GBM). Recent studies have shown that the current treatments not only fail to eliminate the GSC population but even promote GSCs through reprogramming of glioma non-stem cells to stem cells. Since the standard GBM treatment often requires supplementation with adjuvant drugs such as antidepressants, their role in the regulation of the heterogeneous nature of GSCs needs evaluation. METHODS: We examined the effects of imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, escitalopram, and temozolomide on the phenotypic signature (CD44, Ki67, Nestin, Sox1, and Sox2 expression) of GSCs isolated from a human T98G cell line. These drugs were examined in several models of hypoxia (1% oxygen, 2.5% oxygen, and a hypoxia-reoxygenation model) as compared to the standard laboratory conditions (20% oxygen). RESULTS: We report that antidepressant drugs, particularly imipramine and amitriptyline, modulate plasticity, silence the GSC profile, and partially reverse the malignant phenotype of GBM. Moreover, we observed that, in contrast to temozolomide, these tricyclic antidepressants stimulated viability and mitochondrial activity in normal human astrocytes. CONCLUSION: The ability of phenotype switching from GSC to non-GSC as stimulated by antidepressants (primarily imipramine and amitriptyline) sheds new light on the heterogeneous nature of GSC, as well as the role of antidepressants in adjuvant GBM therapy.

Efficacy and safety of cutting balloons for the treatment of obstructive lesions in the internal jugular veins.

BACKGROUND: In this technical note we present the results of endovascular treatment for chronic cerebrospinal venous insufficiency with the use of cutting balloons, with focus on feasibility and safety of these endovascular devices. METHODS: We used cutting balloons during 70 procedures in 65 multiple sclerosis patients presenting with strictures of the internal jugular veins, primarily at the level of jugular valves. These devices were used only in selected cases, following unsuccessful standard balloon angioplasty, and on condition that commercially available devices could be applied (currently they are maximally 8 mm in diameter). RESULTS: In all cases the perioperative course was uneventful, with no serious adverse events. Immediate technical success rate was 94.3%. In four cases (5.7%) cutting-balloon angioplasty alone was unsuccessful and stents were implanted. Primary, assisted primary and secondary patency rates after 6 months were: 94%, 98.5%, and 98.5%, respectively. Follow-up has revealed that out of the remaining 66 angioplasties four procedures failed (failure rate: 6.1%): in two patients stents were implanted, in one patient successful redo cutting-balloon angioplasty was performed, while in another case the treated segment of jugular vein totally occluded and was not feasible to reopen endovascularly. CONCLUSIONS: Cutting balloons can be safely used for the management of stenosed internal jugular veins. These devices can replace stents in the majority of cases, especially if standard balloon angioplasty is insufficient to restore proper outflow. However, the use of cutting balloons in this particular venous territory is limited by the fact that currently only small diameter devices are available.

Ankle-brachial pressure index estimated by laser Doppler in patients suffering from peripheral arterial obstructive disease.

Ankle-brachial index (ABI) measurements are widely used for evaluating the functional state of circulation in the lower limbs. However, there is some evidence that the value of ABI does not accurately reflect the degree of walking impairment in symptomatic patients with peripheral arterial obstructive disease (PAOD). We investigated the diagnostic value of ABI estimated by means of laser Doppler flowmetry (IT) for evaluating limb ischemia. We wanted to know whether laser Doppler could be more sensitive than the Doppler method in predicting walking capacity in patients with stable intermittent claudication. We analyzed a group of 30 patients with intermittent claudication (Fontain II, II/III) who were admitted for reconstructive treatment. There were 21 men and 9 women, aged 46-74 (mean 61) years. All patients underwent the treadmill test, and pain-free walking distances were measured. In each patient, we measured ABI using the two different methods: Doppler ultrasound device (ABI-Doppler) and laser Doppler (ABI-laser Doppler). The claudication distances were 25-200 m (mean 73 +/- 50.2 m). ABI-Doppler was 0.2-0.7 (0.582 +/- 0.195). ABI-laser Doppler measurements were 0.581 (+/-0.218). A correlation was found between ABI-Doppler and claudication distance (r = 0.46, P = 0.009). Also, ABI-laser Doppler values significantly correlated with claudication distances (r = 0.536, P = 0.002). The ABI evaluated by laser Doppler correlated well with claudication distances in patients with PAOD. Comparison of Doppler and laser Doppler measurements used for determining ABI showed that both methods have similar predictive power for walking capacity; however, higher correlation was observed between claudication distances and ABI measured by laser Doppler flowmetry. ABI-laser Doppler measurements are easier, are quicker, and seem to be better suited for noncompliant patients. Further investigation should be undertaken to determine whether laser Doppler is superior to the Doppler method in advanced occlusive arterial disease.