ICE/Caspase-1 inhibitors as novel anti-inflammatory drugs

Randle, John C.R.; Harding, Matthew W.; Ku, George; Schönharting, Martin; Kurrle, R.

doi:10.1517/13543784.10.7.1207

Cited by 87 publications

(47 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…IL-18 is converted from an inactive form (24 kDa) to a bioactive form (18 kDa) upon cleavage by ICE, which was then secreted (29,30). Three murine cell lines, 4T1 breast cancer, CT-26 colorectal cancer, and B16F10 melanoma were tested in this study.…”

Section: Resultsmentioning

confidence: 99%

Multimodality Imaging of IL-18–Binding Protein-Fc Therapy of Experimental Lung Metastasis

Cao

Cai²,

Niu³

et al. 2008

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Interleukin (IL)-18 plays important roles in cancer progression and metastasis.The goal of this study is to identify cell lines that are most sensitive to stand alone IL-18^binding protein (IL-18bp)-Fc treatment, to study the pharmacokinetics and tumor targeting efficiency of IL-18bp-Fc, and to evaluate the efficacy of IL-18bp-Fc in treating breast cancer experimental lung metastasis by multimodality imaging. Experimental Design: Reverse transcription-PCR, ELISA, and other cell-based assays were done on murine 4T1, CT-26, and B16F10 cells. The most IL-18bp-Fc^sensitive 4T1 cells were stably transfected with firefly luciferase (fLuc) and injected i.v. into female BALB/C mice to establish the experimental lung metastasis model. Tumor targeting efficiency and pharmacokinetics of IL-18bp-Fc was assessed by 64 Cu-DOTA-IL-18bp-Fc positron emission tomography (PET) and biodistribution studies. Two groups of fLuc-4T1 experimental lung metastasis tumor-bearing mice were each given saline or IL-18bp-Fc (1 mg/kg) daily i.p. Bioluminescence imaging, 18 F-FDG PET, and computed tomography scans were done to evaluate the treatment efficacy. Ex vivo experiments were also carried out to validate the imaging results. Results: IL-18bp-Fc had high and specific accumulation in the fLuc-4T1lung metastasis tumor as evidenced by both PETand biodistribution studies. Bioluminescence imaging, 18 F-FDG PET, and computed tomography scans all revealed that IL-18bp-Fc treatment was effective in inhibiting the lung metastasis tumor progression, validated by ex vivo examination of the lung. Conclusions: IL-18bp-Fc therapy can inhibit 4T1 breast cancer experimental lung metastasis. Noninvasive multimodality molecular imaging is a powerful tool for evaluating the tumor targeting efficiency/pharmacokinetics of the drug and effective monitoring of the therapeutic response.

show abstract

Section: Resultsmentioning

confidence: 99%

Multimodality Imaging of IL-18–Binding Protein-Fc Therapy of Experimental Lung Metastasis

Cao

Cai²,

Niu³

et al. 2008

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…VX-765, which represents a new class of specific ICE/caspase-1 protease inhibitors, is a prodrug with improved oral bioavailability that has been under clinical development for the treatment of inflammatory and autoimmune conditions [16,37]. VX-765 has been shown to block the release of IL-1β induced by ICE/caspase-1 activation by proinflammatory stimuli in organotypic hippocampal slices [9,38]; moreover, VX-765 reduced acute seizures in kainate-treated rats with a concomitant 50% decrease in hippocampal levels of IL-1β [9].…”

Section: Discussionmentioning

confidence: 99%

“…Using either pralnacasan or VX-765 (two selective inhibitors of interleukin-converting enzyme (ICE)/caspase-1 [16], the key enzyme specifically involved in the production of the releasable and biologically active form of IL-1β [17]), we found a significant decrease in acute seizure activity induced by intracerebral injection of kainic acid [9], and the arrest of seizure generalization in the kindling model of epileptogenesis [12].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

et al. 2011

View full text Add to dashboard Cite

Summary: Experimental evidence and clinical observations indicate that brain inflammation is an important factor in epilepsy. In particular, induction of interleukin-converting enzyme (ICE)/caspase-1 and activation of interleukin (IL)-1β/ IL-1 receptor type 1 axis both occur in human epilepsy, and contribute to experimentally induced acute seizures. In this study, the anticonvulsant activity of VX-765 (a selective ICE/ caspase-1 inhibitor) was examined in a mouse model of chronic epilepsy with spontaneous recurrent epileptic activity refractory to some common anticonvulsant drugs. Moreover, the effects of this drug were studied in one acute model of seizures in mice, previously shown to involve activation of ICE/caspase-1. Quantitative analysis of electroencephalogram activity was done in mice exposed to acute seizures or those developing chronic epileptic activity after status epilepticus to assess the anticonvulsant effects of systemic administration of VX-765.Histological and immunohistochemical analysis of brain tissue was carried out at the end of pharmacological experiments in epileptic mice to evaluate neuropathology, glia activation and IL-1β expression, and the effect of treatment. Repeated systemic administration of VX-765 significantly reduced chronic epileptic activity in mice in a dose-dependent fashion (12.5-200 mg/kg). This effect was observed at doses ≥50 mg/ kg, and was reversible with discontinuation of the drug. Maximal drug effect was associated with inhibition of IL-1β synthesis in activated astrocytes. The same dose regimen of VX-765 also reduced acute seizures in mice and delayed their onset time. These results support a new target system for anticonvulsant pharmacological intervention to control epileptic activity that does not respond to some common anticonvulsant drugs.

show abstract

“…Pralnacasan, an available oral pharmacological ICEI, is used in the field of "classical" inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease in humans as well as in animals models (11,(23)(24)(25)(26). ICE exists as an inactive precursor in the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Pralnacasan is a selective and reversible inhibitor of the interleukin converting enzyme (ICE) (11). ICE, also called caspase-1, is one member of a family of at least 12 human enzymes known as caspases (12).…”

mentioning

confidence: 99%

Cardioprotective and Anti-Inflammatory Effects of Interleukin Converting Enzyme Inhibition in Experimental Diabetic Cardiomyopathy

et al. 2007

View full text Add to dashboard Cite

OBJECTIVE-We investigated the effect of pharmacological inhibition of the interleukin converting enzyme (ICE) on cardiac inflammation, apoptosis, fibrosis, and left ventricular function in an animal model of diabetes.RESEARCH DESIGN AND METHODS-Diabetes was induced in 24 Sprague-Dawley rats by injection of streptozotozin (STZ) (70 mg/kg). Diabetic animals were treated with the interleukin converting enzyme (ICE) inhibitor (ICEI) (n ϭ 12) or with a placebo (n ϭ 12). Nondiabetic rats served as controls (n ϭ 12). Left ventricular function was documented 6 weeks after induction of diabetes. Cardiac tissue was analyzed for the expression of cytokines, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, leukocyte and macrophage integrins, and collagen. Phosphorylation of Akt was analyzed by Western blot and apoptosis by Blc-2 and Bax measurements.RESULTS-Left ventricular function was significantly impaired in diabetic animals. This was accompanied by a significant increase of cytokines, cell adhesion molecules, leukocytes and macrophages, and collagen content. In addition, the phosphorylation state of Akt was reduced. These changes were significantly attenuated in the diabetic group treated with ICEI.CONCLUSIONS-Cardiac dysfunction is associated with cardiac inflammation in experimental diabetic cardiomyopathy. Both of these-cardiac dysfunction and inflammation-are attenuated after treatment with ICEI. These data suggest that anticytokine-based therapies might be beneficial in diabetic cardiomyopathy.

show abstract

ICE/Caspase-1 inhibitors as novel anti-inflammatory drugs

Cited by 87 publications

References 6 publications

Multimodality Imaging of IL-18–Binding Protein-Fc Therapy of Experimental Lung Metastasis

Multimodality Imaging of IL-18–Binding Protein-Fc Therapy of Experimental Lung Metastasis

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

Cardioprotective and Anti-Inflammatory Effects of Interleukin Converting Enzyme Inhibition in Experimental Diabetic Cardiomyopathy

Contact Info

Product

Resources

About