Itraconazole inhibits endothelial cell migration by disrupting inositol pyrophosphate-dependent focal adhesion dynamics and cytoskeletal remodeling

Qi, Ji; Cheng, Weiwei; Gao, Zhe; Chen, Yuanyuan; Shipton, Megan L.; Furkert, David; Chin, Alfred C.; Riley, Andrew M.; Fiedler, Dorothea; Potter, Barry V. L.; Fu, Cheng

doi:10.1016/j.biopha.2023.114449

Cited by 9 publications

(13 citation statements)

References 64 publications

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“…In our study, we found that itraconazole treatment could remodel gene expression and cellular composition, including immune-related cells. The following aspects may account for the findings: (1) itraconazole regulates the lipid metabolism of macrophages and polarization of macrophages 31,32 ; (2) itraconazole exerts anti-angiogenesis by stimulation of apoptosis in endothelial cells, repression the motility of endothelial cells or inhibiting CAF proliferation [33][34][35] ;…”

Section: Discussionmentioning

confidence: 99%

“…In our study, we found that itraconazole treatment could remodel gene expression and cellular composition, including immune‐related cells. The following aspects may account for the findings: (1) itraconazole regulates the lipid metabolism of macrophages and polarization of macrophages 31 , 32 ; (2) itraconazole exerts anti‐angiogenesis by stimulation of apoptosis in endothelial cells, repression the motility of endothelial cells or inhibiting CAF proliferation 33 , 34 , 35 ; (3) itraconazole interferes with the uptake of calcium by activated neutrophils by alteration of glycosylation or glycoprotein processing. 36 , 37 Thus, we speculate that itraconazole may remodel cell composition by directly or indirectly affecting the number or function of macrophages, endothelial cells and neutrophils.…”

Section: Discussionmentioning

confidence: 99%

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Itraconazole inhibits tumor growth via CEBPB‐mediated glycolysis in colorectal cancer

Zhang,

Li,

Chu

et al. 2024

Cancer Science

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Advanced colorectal cancer (CRC) is characterized by a high recurrence and metastasis rate, which is the primary cause of patient mortality. Unfortunately, effective anti‐cancer drugs for CRC are still lacking in clinical practice. We screened FDA‐approved drugs by utilizing targeted organoid sequencing data and found that the antifungal drug itraconazole had a potential therapeutic effect on CRC tumors. However, the effect and mechanism of itraconazole on CRC tumors have not been investigated. A cell line‐derived xenograft model in tumor‐bearing mice was established and single‐cell RNA sequencing was performed on tumor samples from four mice with or without itraconazole treatment. The proportion of cell populations and gene expression profiles was significantly different between the two groups. We found that itraconazole could inhibit tumor growth and glycolysis. We revealed that CEBPB was a new target for itraconazole, and that silencing CEBPB could repress CRC glycolysis and tumor growth by inhibiting ENO1 expression. Clinical analysis showed that CEBPB expression was obviously elevated in CRC patients, and was associated with poor survival. In summary, itraconazole treatment remodeled cell composition and gene expression profiles. Itraconazole inhibited cell glycolysis and tumor growth via the CEBPB–ENO1 axis. In this study, we illustrate a new energy metabolism mechanism for itraconazole on tumor growth in CRC that will provide a theoretical basis for CRC targeting/combination therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Itraconazole inhibits tumor growth via CEBPB‐mediated glycolysis in colorectal cancer

Zhang,

Li,

Chu

et al. 2024

Cancer Science

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“…The BDA-protecting groups were removed with TFA to generate tetraol ( 6) in 88% yield. The benzyl group attached to the 2-position was cleaved via hydrogenation, and the product was lyophilised to generate pentaol (7) in 80% yield. The use of MSE-protecting groups was crucial during this step as they are resistant to hydrogenation, thereby enabling the easy selective removal of only the benzyl group attached to the 2-position.…”

Section: Articlementioning

confidence: 99%

“… 6 The antifungal and anti-angiogenic drug itraconazole requires 5-PP-InsP 5 to inhibit cell motility. 7 Additionally, the participation of the 5-PP-InsP 5 regioisomer, rather than InsP 6 or other inositol pyrophosphates [1-PP-InsP 5 and 1,5-(PP) 2 -InsP 4 ] in glucose homeostasis was demonstrated. 8 5-PP-InsP 5 is thus a G-protein coupled receptor (GPCR) second messenger that is able to regulate synaptotagmin-7 (Syt7) dependent insulin release.…”

Section: Introductionmentioning

confidence: 99%

Expedient synthesis and luminescence sensing of the inositol pyrophosphate cellular messenger 5-PP-InsP₅

et al. 2023

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“…The actin-related protein 2/3 (Arp2/3) is a protein complex responsible for the generation of actin networks at the leading edge of the cell which form lamellipodia protrusions, crucial in neuronal migration and synapse formation [ 100 ]. Coronin binds the p34 subunit of Arp2/3 and inhibits the formation of new actin filaments during remodeling [ 101 , 102 ].…”

Section: Cell Migrationmentioning

confidence: 99%

The Role of Inositol Hexakisphosphate Kinase in the Central Nervous System

Heitmann,

Barrow

2023

Biomolecules

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Inositol is a unique biological small molecule that can be phosphorylated or even further pyrophosphorylated on each of its six hydroxyl groups. These numerous phosphorylation states of inositol along with the kinases and phosphatases that interconvert them comprise the inositol phosphate signaling pathway. Inositol hexakisphosphate kinases, or IP6Ks, convert the fully mono-phosphorylated inositol to the pyrophosphate 5-IP7 (also denoted IP7). There are three isoforms of IP6K: IP6K1, 2, and 3. Decades of work have established a central role for IP6Ks in cell signaling. Genetic and pharmacologic manipulation of IP6Ks in vivo and in vitro has shown their importance in metabolic disease, chronic kidney disease, insulin signaling, phosphate homeostasis, and numerous other cellular and physiologic processes. In addition to these peripheral processes, a growing body of literature has shown the role of IP6Ks in the central nervous system (CNS). IP6Ks have a key role in synaptic vesicle regulation, Akt/GSK3 signaling, neuronal migration, cell death, autophagy, nuclear translocation, and phosphate homeostasis. IP6Ks’ regulation of these cellular processes has functional implications in vivo in behavior and CNS anatomy.

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Itraconazole inhibits endothelial cell migration by disrupting inositol pyrophosphate-dependent focal adhesion dynamics and cytoskeletal remodeling

Cited by 9 publications

References 64 publications

Itraconazole inhibits tumor growth via CEBPB‐mediated glycolysis in colorectal cancer

Itraconazole inhibits tumor growth via CEBPB‐mediated glycolysis in colorectal cancer

Expedient synthesis and luminescence sensing of the inositol pyrophosphate cellular messenger 5-PP-InsP₅

The Role of Inositol Hexakisphosphate Kinase in the Central Nervous System

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Itraconazole inhibits endothelial cell migration by disrupting inositol pyrophosphate-dependent focal adhesion dynamics and cytoskeletal remodeling

Cited by 9 publications

References 64 publications

Itraconazole inhibits tumor growth via CEBPB‐mediated glycolysis in colorectal cancer

Itraconazole inhibits tumor growth via CEBPB‐mediated glycolysis in colorectal cancer

Expedient synthesis and luminescence sensing of the inositol pyrophosphate cellular messenger 5-PP-InsP5

The Role of Inositol Hexakisphosphate Kinase in the Central Nervous System

Contact Info

Product

Resources

About

Expedient synthesis and luminescence sensing of the inositol pyrophosphate cellular messenger 5-PP-InsP₅