Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor

Puxeddu, Michela; Wu, Jianchao; Bai, Ruoli; D’Ambrosio, Michele; Nalli, Marianna; Coluccia, Antonio; Manetto, Simone; Ciogli, Alessia; Masci, Domiziana; Urbani, Andrea; Fionda, Cinzia; Coni, Sonia; Bordone, Rosa; Canettieri, Gianluca; Bigogno, Chiara; Dondio, Giulio; Hamel, Ernest; Liu, Te; Silvestri, Romano; Regina, Giuseppe La

doi:10.1021/acs.jmedchem.2c01457

Cited by 15 publications

(7 citation statements)

References 71 publications

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“…Sulfonamides 10−13 were prepared as depicted in Scheme 1. 3-Aroylpyrroles 10 and 11 were synthesized starting by reaction of ketones 22 or 23 34 with the 2-(trimethylsilyl)ethoxymethyl (SEM) protected 4-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (24) in the presence of copper(I) iodide, cesium carbonate, and 1,10-phenanthroline under microwave irradiation at 210 °C, 200 W for 40 min to give 4-(3-benzoyl-1H-pyrrol-1-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-benzenesulfonamide (27) or the corresponding 3-(3′,4′,5′-trimethoxybenzoyl-1H-pyrrol-1-yl) derivative (28). Similarly, 29 and 30 were obtained starting from 23 and 3-bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (25) or 2bromo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)benzenesulfonamide (26), respectively.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Sulfonamides 14−21 were prepared by similar routes, as depicted in Scheme 2. Compounds 14−17 were synthesized starting from 3-aroyl-4-phenylpyrroles 31 35 and 32 34 (Scheme Biology. Inhibition of hCA I, hCA II, hCA IX, and hCA XII Isoforms.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Sulfonamides 14 – 21 were prepared by similar routes, as depicted in Scheme 2 . Compounds 14 – 17 were synthesized starting from 3-aroyl-4-phenylpyrroles 31 ( 35 ) and 32 ( 34 ) ( Scheme 2 , panel A) and 18 – 21 starting from 3-aroylindoles 37 and 38 ( 36 ) ( Scheme 2 , panel B).…”

Section: Resultsmentioning

confidence: 99%

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4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

Masci,

Puxeddu,

Di Magno

et al. 2023

J. Med. Chem.

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We synthesized new pyrrole and indole derivatives as human carbonic anhydrase (hCA) inhibitors with the potential to inhibit the Wnt/β-catenin signaling pathway. The presence of both N1-(4-sulfonamidophenyl) and 3-(3,4,5-trimethoxyphenyl) substituents was essential for strong hCA inhibitors. The most potent hCA XII inhibitor 15 (K i = 6.8 nM) suppressed the Wnt/βcatenin signaling pathway and its target genes MYC, Fgf20, and Sall4 and exhibited the typical markers of apoptosis, cleaved poly(ADP-ribose)polymerase, and cleaved caspase-3. Compound 15 showed strong inhibition of viability in a panel of cancer cells, including colorectal cancer and triple-negative breast cancer cells, was effective against the NCI/ADR-RES DOX-resistant cell line, and restored the sensitivity to doxorubicin (DOX) in HT29/DX and MDCK/P-gp cells. Compound 15 is a novel dual-targeting compound with activity against hCA and Wnt/β-catenin. It thus has a broad targeting spectrum and is an anticancer agent with specific potential in P-glycoprotein overexpressing cell lines.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

See 1 more Smart Citation

4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

Masci,

Puxeddu,

Di Magno

et al. 2023

J. Med. Chem.

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“…At present, there are few studies on the function of TUBE1. Tubulin is thought to be stimulated of oxidative stress injury and Fe 2+ accumulation, which displays inhibition of cancer cell proliferation 24 . Moreover, blocking tubulin-dependent mitochondrial depolarization could enhance ROS formation and ROS-related mitochondrial dysfunction like erastin do 25 .…”

Section: Discussionmentioning

confidence: 99%

Analysis and verification of ferroptosis-related genes in pediatric hepatoblastoma

Ye,

Chen,

Xia

et al. 2024

Preprint

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Background Identifying effective biomarker in hepatoblastoma (HB) is important for predicting prognosis. This study committed to investigate the prognostic value of ferroptosis-related genes (FRGs) in HB. Methods and Results The two datasets of pediatric HB were obtained from Gene Expression Omnibus (GEO) database and analyzed differentially expressed genes (DEGs). Functional enrichment analysis was performed for these DEGs. Weighted gene co-expression network analysis (WGCNA) was used to screen the key modules. FRGs were obtained from the ferroptosis database. Subsequently, after identified of the candidate hub genes by the intersection of DEGs, key module genes and FRGs, least absolute shrinkage and selection operator (LASSO) and receiver operating characteristic (ROC) curves were finally applied to identify the hub genes. Two hub genes, TRL4 and TUBE1, were obtained with the AUC of 0.940 and 0.932. The gene set enrichment analysis (GSEA) was exerted to explore the signaling pathways related to the hub genes. The promoted expression of two hub genes in ferroptosis inducer, erastin-treated HB cell lines was verified via real-time qPCR. The effect of hub genes on viability and ferroptosis of HB cell line was verified in vitro. Specifically, the silence of TRL4 and TUBE1 could inhibit the ferroptosis and reverse the proliferation inhibition of HepG2 cells under erastin treating. Conclusion Ferroptosis-related genes TRL4 and TUBE1 emerge remarkable prognostic performance in pediatric HB as well as therapeutic target in the future. TRL4 and TUBE1 could function as tumor inhibiting factors in HB by promoting cell proliferation and prohibiting ferroptosis.

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“…[ 40 ] Together with VEGF, CD31 is a well‐defined angiogenic marker and shows high expression on the surface of endothelial cells, which is implicated with angiogenesis in many types of cancer, such as breast cancer, [ 41 ] glioblastoma, and ovarian cancer. [ 42 ] It has been demonstrated that the impact of lactic acid on tumor angiogenesis is the consequence of the interaction between vascular endothelial cells and tumor cells. [ 43 ] Our findings illuminated that both lactate and glucose stimulation counteracted the suppressive effect of FGF6 depletion on the viability, migratory ability, and tube formation of HUVECs cocultured with BC cell supernatants and tube formation capacity of BC cells.…”

Section: Discussionmentioning

confidence: 99%

Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways

Zhi

Cai

et al. 2023

J Biochem & Molecular Tox

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Metabolic abnormalities and uncontrolled angiogenesis are two vital features of malignant tumors. Although fibroblast growth factor 6 (FGF6) is known to promote the proliferation and migration of bladder cancer (BC) cells, its influences on aerobic glycolysis and angiogenesis in BC remain unclear. Gene expression at messenger RNA and protein levels were examined by reverse transcription‐quantitative polymerase chain reaction and Western blot analyses, respectively. Lactate production and glucose uptake in BC cells were evaluated by performing aerobic glycolysis assays. A vasculogenic mimicry assay was executed for assessing the angiogenesis of BC cells. The viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) cocultured with supernatants of BC cells were detected using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, wound healing assay, and tube formation assay. It was found that FGF6 displayed a high level in BC cell lines. Silencing of FGF6 reduced the levels of lactate production, glucose uptake, and the expression of angiogenic factors and glycolytic enzymes in BC cells, which also inhibited the viability and migration of HUVECs. In addition, FGF6 depletion or aerobic glycolysis inhibitor 2‐deoxy‐d‐glucose treatment decreased the total branching length and intersection number of both BC cells and HUVECs. Moreover, glucose or lactate treatment reversed FGF6‐induced suppression of cell viability, migration, tube formation, and vasculogenic mimicry. The activation of the phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (Akt) and mitogen‐activated protein kinase (MAPK) signaling pathways was blocked by silenced FGF6. Furthermore, PI3K/Akt inhibitor (LY2940002) and p38‐MAPK inhibitor (SB203580) inhibited the levels of aerobic glycolysis‐related proteins. In conclusion, FGF6 knockdown suppressed aerobic glycolysis, thereby inhibiting angiogenesis in BC via regulation of the PI3K/Akt and MAPK signaling pathways.

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Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor

Cited by 15 publications

References 71 publications

4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

Analysis and verification of ferroptosis-related genes in pediatric hepatoblastoma

Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways

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