The indirubin derivative 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference

Czapka, Anna; König, Stefanie; Pergola, Carlo; Grune, Christian; Vougogiannopoulou, Konstantina; Skaltsounis, Alexios‐Léandros; Fischer, Dagmar; Werz, Oliver

doi:10.1016/j.bcp.2020.114170

Cited by 13 publications

(24 citation statements)

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“…To assess detrimental effects of 6BIGOE and 6BIGOE-loaded NPs prepared by different formulation methods, we analyzed the viability of human monocytes after 24 or 48 h incubations using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. While after 24 h the apoptosis-inducer staurosporine (STSP, 1 µM) significantly decreased cell viability, no significant cytotoxic effects were evident for 6BIGOE at concentrations up to 1 µM, although 6BIGOE significantly reduced cell viability at 3 µM in agreement with results obtained before [ 11 ]. Notably, 6BIGOE-NPs prepared by either formulation method did not affect monocyte viability within 24 h over the complete concentration range up to 3 µM (Fig.…”

Section: Resultssupporting

confidence: 88%

“…Indirubin and its synthetic analogues are well-established inhibitors of cyclin-dependent kinases, dual-specificity tyrosine-regulated kinases, aurora kinases, and glycogen synthase kinase (GSK)-3 [ 2 – 4 ], and therefore offer a broad therapeutic potential for the treatment of various disorders ranging from inflammatory [ 5 , 6 ], autoimmune [ 7 ], metabolic [ 8 ] and neurodegenerative diseases [ 9 ] to cancer [ 10 ]. Among these indirubins, 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) was identified as a highly potent and favorable modulator of inflammatory cytokines and lipid mediators (LMs) in human monocytes and thus, represents an interesting candidate for the treatment of inflammation-related diseases [ 11 ]. However, 6BIGOE and its close structural derivative 6-bromoindirubin-3'-oxime (6BIO) exhibit cytotoxic effects [ 3 , 12 , 13 ] and suffer from poor water solubility, low stability, and short half-life times in blood [ 11 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Among these indirubins, 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) was identified as a highly potent and favorable modulator of inflammatory cytokines and lipid mediators (LMs) in human monocytes and thus, represents an interesting candidate for the treatment of inflammation-related diseases [ 11 ]. However, 6BIGOE and its close structural derivative 6-bromoindirubin-3'-oxime (6BIO) exhibit cytotoxic effects [ 3 , 12 , 13 ] and suffer from poor water solubility, low stability, and short half-life times in blood [ 11 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Drug delivery of 6-bromoindirubin-3’-glycerol-oxime ether employing poly(d,l-lactide-co-glycolide)-based nanoencapsulation techniques with sustainable solvents

et al. 2022

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Background Insufficient solubility and stability of bioactive small molecules as well as poor biocompatibility may cause low bioavailability and are common obstacles in drug development. One example of such problematic molecules is 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE), a hydrophobic indirubin derivative. 6BIGOE potently modulates the release of inflammatory cytokines and lipid mediators from isolated human monocytes through inhibition of glycogen synthase kinase-3 in a favorable fashion. However, 6BIGOE suffers from poor solubility and short half-lives in biological aqueous environment and exerts cytotoxic effects in various mammalian cells. In order to overcome the poor water solubility, instability and cytotoxicity of 6BIGOE, we applied encapsulation into poly(d,l-lactide-co-glycolide) (PLGA)-based nanoparticles by employing formulation methods using the sustainable solvents Cyrene™ or 400 g/mol poly(ethylene glycol) as suitable technology for efficient drug delivery of 6BIGOE. Results For all preparation techniques the physicochemical characterization of 6BIGOE-loaded nanoparticles revealed comparable crystallinity, sizes of about 230 nm with low polydispersity, negative zeta potentials around − 15 to − 25 mV, and biphasic release profiles over up to 24 h. Nanoparticles with improved cellular uptake and the ability to mask cytotoxic effects of 6BIGOE were obtained as shown in human monocytes over 48 h as well as in a shell-less hen’s egg model. Intriguingly, encapsulation into these nanoparticles fully retains the anti-inflammatory properties of 6BIGOE, that is, favorable modulation of the release of inflammation-relevant cytokines and lipid mediators from human monocytes. Conclusions Our formulation method of PLGA-based nanoparticles by applying sustainable, non-toxic solvents is a feasible nanotechnology that circumvents the poor bioavailability and biocompatibility of the cargo 6BIGOE. This technology yields favorable drug delivery systems for efficient interference with inflammatory processes, with improved pharmacotherapeutic potential. Graphical Abstract

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Drug delivery of 6-bromoindirubin-3’-glycerol-oxime ether employing poly(d,l-lactide-co-glycolide)-based nanoencapsulation techniques with sustainable solvents

et al. 2022

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“…In the context of viral infection, human hepatic CSCs (Huh7, JFH-1-Huh7, Huh7.5, and MH14C) treated with BIO and infected with HCV suffered an impairment of IFN signaling via inhibition of signal transducer and activator of transcription 1 (STAT1) phosphorylation and degradation ( 51 ). Also, a BIO analog 6BIGOE inhibited LPS (UO)-induced release of the pro inflammatory cytokines IL-1β, IL-6, and TNF-α, chemokine IL-8, and prostaglandin (PG) in human primary monocytes while increasing β-catenin and IL-10 levels via intracellular inhibition of GSK3 ( 52 ) ( Table S1 ) .…”

Section: Strategies To Inhibit the Inflammatory Response By Gsk3β Inhibitionmentioning

confidence: 99%

Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites

et al. 2021

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Knowledge of glycogen synthase kinase 3β (GSK3β) activity and the molecules identified that regulate its function in infections caused by pathogenic microorganisms is crucial to understanding how the intensity of the inflammatory response can be controlled in the course of infections. In recent years many reports have described small molecular weight synthetic and natural compounds, proteins, and interference RNA with the potential to regulate the GSK3β activity and reduce the deleterious effects of the inflammatory response. Our goal in this review is to summarize the most recent advances on the role of GSK3β in the inflammatory response caused by bacteria, bacterial virulence factors (i.e. LPS and others), viruses, and parasites and how the regulation of its activity, mainly its inhibition by different type of molecules, modulates the inflammation.

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“…Interestingly, 3 was able to suppress pro-inflammatory genes, including IL-1α, IL-1β, IL-12, prostaglandin endoperoxide synthase 2 (PTGS-2), and Toll-like receptor 4 (TLR4), as well as the secretion of the pro-inflammatory cytokine IL-6 in LN-18 and T98G glioblastoma cells [ 137 ]. Similarly, 6-bromoindirubin-3′-glycerol-oxime ether suppressed LPS-induced secretion of IL-1β and PGE 2 via the inhibition of GSK-3β [ 138 ]. Unexpectedly, compound 4 appears to be a strong dual inhibitor of JAK/signal transducer and activator of transcription 3 (STAT3) and Src family of protein tyrosine kinases (SFKs)/STAT3 signaling that is associated with the induction of apoptosis in human pancreatic cancer cells [ 47 , 139 ].…”

Section: Indirubin Oxime-based Kinase Inhibitorsmentioning

confidence: 99%

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

et al. 2021

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Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.

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The indirubin derivative 6-bromoindirubin-3′-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference

Cited by 13 publications

References 44 publications

Drug delivery of 6-bromoindirubin-3’-glycerol-oxime ether employing poly(d,l-lactide-co-glycolide)-based nanoencapsulation techniques with sustainable solvents

Drug delivery of 6-bromoindirubin-3’-glycerol-oxime ether employing poly(d,l-lactide-co-glycolide)-based nanoencapsulation techniques with sustainable solvents

Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

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