Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

Zanfirescu, Anca; Ungurianu, Anca; Mihai, Dragoș Paul; Radulescu, Denise; Nițulescu, George Mihai

doi:10.3390/molecules26185668

Cited by 20 publications

(13 citation statements)

References 129 publications

(214 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since AM9928 inhibited tumor growth in the mammary fat pads (Fig. 4 ) and prevented changes in BBB integrity in vivo , resulting in reduced tumor cell colonization in brain, we conclude that MAGL plays a role in TNBC tumor growth and TNBC transmigration across the BBB, in addition to its roles in neurological and neurodegenerative diseases 25 , 26 . Since metastasis to the brain was reported to be associated with damage to the cranial bone (osteolysis) 1 – 3 , it is important to investigate whether AM9928 may have bone protective effects in mice bearing the GFP-4T1-BrM5 cells.…”

Section: Discussionmentioning

confidence: 69%

Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase

Benchama

Tyukhtenko

Malamas

et al. 2022

Sci Rep

View full text Add to dashboard Cite

While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to generation of pro- and anti-inflammatory molecules. Here, we targeted MAGL in TNBCs, using a potent carbamate-based inhibitor AM9928 (hMAGL IC50 = 9 nM) with prolonged pharmacodynamic effects (46 h of target residence time). AM9928 blocked TNBC cell adhesion and transmigration across human brain microvascular endothelial cells (HBMECs) in 3D co-cultures. In addition, AM9928 inhibited the secretion of IL-6, IL-8, and VEGF-A from TNBC cells. TNBC-derived exosomes activated HBMECs resulting in secretion of elevated levels of IL-8 and VEGF, which were inhibited by AM9928. Using in vivo studies of syngeneic GFP-4T1-BrM5 mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat pads and attenuated blood brain barrier (BBB) permeability changes, resulting in reduced TNBC colonization in brain. Together, these results support the potential clinical application of MAGL inhibitors as novel treatments for TNBC.

show abstract

Section: Discussionmentioning

confidence: 69%

Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase

Benchama

Tyukhtenko

Malamas

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Since AM9928 inhibited tumor growth in the mammary fat pads (Figure 4) and prevented changes in BBB integrity in vivo, resulting in reduced tumor cell colonization in brain, we conclude that MAGL plays a role in TNBC tumor growth and TNBC transmigration across the BBB, in addition to its roles in neurological and neurodegenerative diseases. 51,53 Taken together, we suggest that targeting MAGL may provide a new approach to reducing expression of proinflammatory factors as well as inhibiting tumor growth and tumor cell colonization in brain.…”

Section: Discussionmentioning

confidence: 86%

“…24 Recently, 2-AG was shown to be the source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. 45,51,53 Accumulated studies showed that MAGL inhibition impaired cell migration, invasion and tumorigenicity in some types of cancers. 20,[22][23][24] Further, MAGL promoted progression of hepatocellular carcinoma via NF-kB mediated epithelial-mesenchymal transition.…”

mentioning

confidence: 99%

Targeting Monoacylglycerol Lipase in Triple Negative Breast Cancer Reduced Tumor-Associated Inflammation, Tumor Growth and Tumor Colonization in the Brain

Benchama

Tyukhtenko

Malamas

et al. 2021

Preprint

View full text Add to dashboard Cite

While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to generation of pro- and anti-inflammatory molecules. Here, we targeted MAGL in TNBCs, using the selective MAGL inhibitor AM9928 (hMAGL IC50 = 9nM, with prolonged pharmacodynamic effects of 46 hours residence time). AM9928 blocked TNBC cell adhesion and transmigration across human brain microvascular endothelial cells (HBMECs) in 3D co-cultures. In addition, AM9928 inhibited the secretion of IL-6, IL-8, and VEGF-A from TNBC cells. TNBC-derived exosomes activated HBMECs resulting in secretion of elevated levels of IL-8 and VEGF, which were inhibited by AM9928. Knockdown of MAGL by siRNA or treatment with AM9928 increased the expression of the adherent junction E-cadherin, known to be regulated by MAGL. Using in vivo studies of syngeneic GFP-4T1-BrM5 mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat pads and attenuated blood brain barrier (BBB) permeability changes, resulting in reduced TNBC colonization in brain. Together, these results support the potential clinical application of MAGL inhibitors as novel treatments for TNBC.

show abstract

“…The proteins were prepared by adding polar hydrogen atoms, and gasteiger charges before docking were processed in MGL Tools. The AutoDock Vina software was used to perform the docking analysis [25]. The size and dimension of the Grid box was selected using co-crystalized ligand coordinates within the target protein [26].…”

Section: Docking Protocolmentioning

confidence: 99%

Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plant Compounds by Targeting TLR-4/AP-1 Signaling: A Comprehensive Molecular Docking and Simulation Approaches

Khan

et al. 2022

Molecules

View full text Add to dashboard Cite

Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin’s greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood–brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.

show abstract

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

Cited by 20 publications

References 129 publications

Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase

Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase

Targeting Monoacylglycerol Lipase in Triple Negative Breast Cancer Reduced Tumor-Associated Inflammation, Tumor Growth and Tumor Colonization in the Brain

Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plant Compounds by Targeting TLR-4/AP-1 Signaling: A Comprehensive Molecular Docking and Simulation Approaches

Contact Info

Product

Resources

About