Meizothrombin, an intermediate of prothrombin activation, stimulates human glioblastoma cells by interaction with PAR-1-type thrombin receptors

Kaufmann, Roland; Zieger, Michael; Tausch, Svetlana; Henklein, Peter; Nowak, G

doi:10.1002/(sici)1097-4547(20000301)59:5<643::aid-jnr7>3.0.co;2-g

Cited by 12 publications

(3 citation statements)

References 41 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human gliomas express prothrombin [74] and meizothrombin an intermediate of prothrombin activation stimulates glioblastoma cells by interaction with PAR-1 type thrombin receptors [75]. Glioblastoma cell lines have been found to express PAR-1 and 2 [76].…”

Section: Par-2 In Cancermentioning

confidence: 99%

Common critical pathways in embryogenesis and cancer

2006

View full text Add to dashboard Cite

Section: Par-2 In Cancermentioning

confidence: 99%

Common critical pathways in embryogenesis and cancer

2006

View full text Add to dashboard Cite

“…Thrombin activity is increased in high-grade glioma and non-glial malignant CNS tumor cell lines [223]. Meizothrombin stimulates human glioblastoma cells via interaction with PAR1 [224]. Tumor precursor cells derived from primary human gliomas and glioblastoma cells overexpress PAR1 [225][226][227].…”

Section: Primary Cns Tumorsmentioning

confidence: 99%

Role of Thrombin in Central Nervous System Injury and Disease

et al. 2021

View full text Add to dashboard Cite

Thrombin is a Na+-activated allosteric serine protease of the chymotrypsin family involved in coagulation, inflammation, cell protection, and apoptosis. Increasingly, the role of thrombin in the brain has been explored. Low concentrations of thrombin are neuroprotective, while high concentrations exert pathological effects. However, greater attention regarding the involvement of thrombin in normal and pathological processes in the central nervous system is warranted. In this review, we explore the mechanisms of thrombin action, localization, and functions in the central nervous system and describe the involvement of thrombin in stroke and intracerebral hemorrhage, neurodegenerative diseases, epilepsy, traumatic brain injury, and primary central nervous system tumors. We aim to comprehensively characterize the role of thrombin in neurological disease and injury.

show abstract

“…1) and is mediated by a number of trypsin-fold serine proteases (Table 1) including thrombin (Vu et al, 1991) and pro-thrombin intermediates (Kaufmann et al, 1998(Kaufmann et al, , 2000, granzyme A (Suidan et al, 1994), plasmin (Kuliopulos et al, 1999), activated protein C (APC (Riewald et al, 2002)), factor Xa (FXa ), trypsin IV and members of the kallikreinrelated peptidase (KLK) family, including tissue kallikrein/KLK1 (Gao et al, 2010a(Gao et al, , 2010b), KLK4 (Mize et al, 2008;Ramsay et al, 2008a;Gratio et al, 2010), KLK5, 6 and 14 (Oikonomopoulou et al, 2006). Cathepsin G which displays both chymotryptic and tryptic substrate specificity (i.e.…”

Section: Protease Agonists and Dis-armersmentioning

confidence: 99%

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Yau¹

View full text Add to dashboard Cite

About 30-40% of all drugs currently in the market place target G-protein coupled receptors, however of the 900 plus GPCRs predicted to exist only about 30 are targeted by approved drugs. Two novel human GPCRs were investigated in this thesis, namely protease-activated receptor 2 (PAR2) and C3a receptor (C3aR). These membranebound receptors are implicated in a variety of diseases in which inflammation is a common component, making them attractive targets for drugs that can treat such disorders. This thesis describes the rational design, synthesis and in vitro assay of ligands targeting these two GPCRs and they will become useful probes for investigating the pathology of inflammatory disorders and may lead to possible future treatments.Chapter 1 of this thesis summarises peptidic and non-peptidic ligands for proteaseactivated receptor and C3a receptor reported in the literature to date, together with their known physiological effects.Chapter 2 examines structure-activity relationships for analogues of the only known potent PAR2 antagonist (GB88) discovered at IMB. The chemical features of GB88 were investigated separately by dividing the molecule into fragments, which were independently varied to study the effect of structure on agonist/antagonist function of the ligands. A potent and selective PAR2 agonist (132) was developed with EC 50 of 0.4 µM in calcium release assays on HT29 cells. Agonist 132 has comparable agonist potency and better ligand efficiency to 2f-LIGRLO-NH 2 , which was previously the most potent PAR2 agonist prior to these studies. In addition, a new PAR2 antagonist was developed (167), which was 2-fold more potent than GB88 in the calcium mobilisation assay.Chapter 3 describes the non-peptidic PAR2 agonist (GB110) and SAR studies for the truncation of this compound that led to the development of new PAR2 antagonists (192, 209, 211, 212). These ligands inhibited the activation of PAR2 induced by 1 µM 2f-LIGRLO-NH 2 with IC 50 0.4-0.6 µM in the calcium release assay.Chapter 4 evaluates the anti-inflammatory properties of newly developed PAR2antagonists (133, 159, 167, 192 -from Chapters 2 & 3) in both in vivo and in vitro experiments. The most potent PAR2 antagonists (167 and 192) were stable in rat plasma and rat liver homogenates and were able to inhibit PAR2 activation induced by peptide agonist 2f-LIGRLO-NH 2 as well as the endogenous activator, trypsin. These iv antagonists have been demonstrated to be anti-inflammatory agents, inhibiting proinflammatory cytokine release (IL6 and TNF-α) and were effective in relieving joint inflammation in rat models of arthritis.Chapter 5 explores various aromatic heterocycles that confer a turn conformation to ligands and this mimics the turn conformation observed for the C-terminus of C3a in its crystal structure. The study investigates how the hydrogen bonding capabilities of heteroatoms in each heterocycle affect the binding and functions of the ligands.Increasing the hydrogen bond acceptor properties of the heterocycle improves binding affinity...

show abstract

Meizothrombin, an intermediate of prothrombin activation, stimulates human glioblastoma cells by interaction with PAR-1-type thrombin receptors

Cited by 12 publications

References 41 publications

Common critical pathways in embryogenesis and cancer

Common critical pathways in embryogenesis and cancer

Role of Thrombin in Central Nervous System Injury and Disease

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Contact Info

Product

Resources

About