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Biphalin is a new type of opioid peptide analogue with high analgesic potency that is over 1000-fold greater than morphine, a well-known opiate compound widely utilized in pain management. Because of its less addictive nature than morphine, this substance has been suggested as an useful analgesic drug. Biphalinís high analgesic activity may be related with interaction with all three types of opioid receptors (mu, delta and kappa), belonging to G proteincoupled receptors (GPCR) family. These members of GPCR are expressed by astrocytes, including neoplastic glioma cells. It has been evidenced, that opioid receptors, particularly MOR (mu opioid receptor) and KOR (kappa opioid receptor) are involved in growth regulation of glioma cells. The alteration of tumor cell proliferation might be associated with adenylate cyclase inhibition, that results in decrease of intracellular cAMP level and prevention of PKA activation. The present study was performed on human glioblastoma cell line TG98 to establish the effect of biphalin on neoplastic cell growth and proliferation abilities. The glioma cell line exposed to biphalin at increasing concentrations exhibited the decrease of growth rate, reduction of cell ability to form colonies and alteration of Ki-67 proliferation index. These results suggest that this opioid peptide analogue is promising medicine in simultaneous analgesic and anti-cancer therapy. The work was supported by the Ministry of Science and Education, Grant No. NN401228334 and European Grant Normolife No. LSHC-CT-2006-037733.
Gliomas are the most common primary brain tumours characterized by infiltrative cell growth. The specific novelty inhibitors of constitutively active serine/threonine kinase (CK2), i.e. isothiourea derivatives induce apoptosis and affect proliferation in some human cancer cells. We examined the cytotoxic and proapoptotic effect of selected modified isothiourea derivatives – pentabromobenzylisothioureas (ZKKs) against T98G adult human glioblastoma cell lines and cultures derived from rare, low-grade pediatric brain tumour of a mixed glioneuronal lineage (subependymal giant cell astrocytoma – SEGA), and normal human cultured astrocytes. ZKK-3 and ZKK-2 appeared to be the most effective compounds that induce apoptosis and exhibit strong anti-proliferative effect on neoplastic astroglial cells determined by flow cytometry analysis and Multisizer3 Beckman Coulter. Treatment of T98G cell line and SEGAderived cell cultures with 50 µM ZKK-3 and ZKK-2 for 48 h resulted in apoptosis and inhibition of cell proliferation up to 60% and 50% respectively. These results might suggest the potential anti-tumour effect of selected ZKKs related with glioma-derived neoplasms.
BACKGROUND AND AIMS: Gliomas, derived from astroglial cells, constitute about 50% of all brain tumours. The hypoxic state of neoplastic tissue is regarded to be an important reason of treatment failure with chemo- and radiotherapy. The aim of this study was to examine if administration of gas mixture with increased and decreased oxygen content will result in changes of cytotoxic properties of modified isothiourea derivative (ZKK-3) against human glioblastoma tumour in vitro. METHODS: The experiment was performed on human glioblastoma T98G cell line, which were cultured in hypoxic (for 24 hours) or hyperbaric oxygen conditions (HBO, 1 hour of hyperbaric oxygen under the pressure of 3 ATA, then 23 hours of normoxia) in a medium containing selected modified isothiourea derivative: N,N’- dimethyl-S-(2,3,4,5,6-pentabromobenzyl)-isothiouronium bromide (ZKK-3). Control cultures were preserved in standard conditions. The viability of the cells was evaluated after 24 and 48 hours using CellTiter 96® AQueous One Solution Cell Proliferation Assay (Promega). Cell proliferation was assessed after 24 hours by Multisizer 3 Beckman Coulter. RESULTS: Glioma cells subjected to hypoxia conditions were significantly more resistant to cytotoxic action of ZKK-3. The proliferative rate of neoplastic glioma cells appeared not to be affected when the cultures were exposed to low oxygen partial pressure. The HBO treatment resulted in enhancement of anti-tumour properties of tested isothiourea derivative, evidenced by a decrease in T98G cells viability and growth. CONCLUSIONS: Hypoxia culture conditions reduce the therapeutic effect of ZKK-3 and promote glioma cells survivability, which is possibly associated with the induction of drug resistance. Increase of sensitivity of glioma cells to the tested agent after administration of hyperbaric oxygen allows to consider HBO as a promising therapeutic strategy for patients with gliomas. The research was supported by the KNOW-MMRC project.
BACKGROUND AND AIMS: Gliomas are the most common primary brain tumours. The malignant gliomas is characterized by infiltrative growth related with poor prognosis. The therapy of astroglial tumours remains still challenging. Protein kinase (CK2) inhibitors have been suggested as promising drugs for antitumour therapy. CK2 (known as caseine kinase II) is an ubiquitous Ser/ Thr protein kinase present in both the nucleus and the cytoplasm of neoplastic cells. CK2 has been frequently found to be deregulated (mostly hyperactivated) in malignancies. It plays a role in cell survival, proliferation and can exert an anti-apoptotic role by protecting regulatory proteins from caspase-mediated degradation. The aim of this study was to evaluate the cytostatic effect of novel CK2 inhibitors on cell lines of human glial tumours. METHODS: The study was performed on human glioblastoma cell line (T98G) and cell lines derived from subependymal giant cell astrocytoma (SEGA) – a low-grade pediatric brain tumour. The tested compound included selected CK2 inhibitors: TBIAEA, DMAT, TBI and TBB. We analyzed the cell viability (MTT metabolism assay) and cell proliferation (Multisizer3 Beckman Coulter cell counter). RESULTS: The marked decrease of a total number of neoplastic cells was observed in all experimental groups, especially after 24 and 48 hours of treatment. TBIAEA appeared to be the most effective compounds that exhibit a strong anti-proliferative effect on neoplastic astroglial cells in gliomas of low and high grade malignancy in vitro. It most effectively inhibited the viability of cultured glioma cells after 24 hours at concentration 25–100 µM. CONCLUSIONS: The results show that selected CK2 inhibitors have a potent antiproliferative efficacy against human malignant glioma cells. It may offer a promising anti-tumour therapy, including treatment of glioma-derived primary brain tumours. The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw
In the present study we investigated the effect of dual endothelin receptor (ETR) antagonist bosentan on postischemic structural abnormalities of subcellular organelles in neurons of cerebral cortex and on endothelin binding sites in the brain after 10 min of cardiac arrest in male Wistar rats. After seven days, cortical neurons in bosentantreated animals revealed diminished morphological changes compared with non-treated rats, including less advanced nuclear pore formation, disaggregation of ribosomes, abnormalities of Golgi network and better preservation of long neurotubules. The analysis of 125I-endothelin-1 binding in brain documented a decrease in endothelin-1 maximum density of receptors (Bmax) and equilibrium dissociation constant (KD) up to 1 week in untreated animals. In bosentan-treated animals above values increased postischemically. In conclusion, the results indicate that bosentan works towards salvage of cytoskeleton and other organelles of cortical neurons after cardiac arrest through a modulation of ETR signaling.
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