Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification

Carbone, Daniela; Vestuto, Vincenzo; Ferraro, Maria Rosalia; Ciaglia, Tania; Pecoraro, Camilla; Sommella, Eduardo; Cascioferro, Stella; Salviati, Emanuela; Novi, Sara; Tecce, Mario Felice; Amodio, Giuseppina; Iraci, Nunzio; Cirrincione, Girolamo; Campiglia, Pietro; Diana, Patrizia; Bertamino, Alessia; Parrino, Barbara; Ostacolo, Carmine

doi:10.1016/j.ejmech.2022.114233

Cited by 33 publications

(22 citation statements)

References 55 publications

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“…Among the amino acids, glutamine m/z 145.06 and glutamate m/z 146.04, previously associated with oral cavity carcinoma [42,43], significantly increased in the parotid tumor region. This is consistent with the recognized importance of glutamine in the bioenergetics request of cancerous cells [9]. Moreover, upon its conversion to glutamate, glutamine provides a key source of carbon for the TCA cycle [44].…”

Section: Metabolome Differences Between Tumor and Non-tumor Areas Of ...supporting

confidence: 84%

“…Metabolic reprogramming is a hallmark of cancer and can be exploited for both diagnostic and therapeutic purposes [7,8]. In this regard, mass spectrometry-based metabolomics allows for monitoring the main molecular changes related to cancer cell signaling, disease onset mechanisms, and tumor progression [9], and has increasingly emerged as a valid tool for early diagnosis and to identify predictive biomarkers of cancer [10]. Gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) are usually employed for metabolome analyses of clinical samples [11,12], even though high-resolution mass spectrometry (HRMS) in direct infusion (DI) and/or coupled to ultra-high performance liquid chromatography (UHPLC-HRMS) has become the gold standard for metabolomics [13].…”

Section: Introductionmentioning

confidence: 99%

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MALDI Mass Spectrometry Imaging Highlights Specific Metabolome and Lipidome Profiles in Salivary Gland Tumor Tissues

et al. 2022

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Salivary gland tumors are relatively uncommon neoplasms that represent less than 5% of head and neck tumors, and about 90% are in the parotid gland. The wide variety of histologies and tumor characteristics makes diagnosis and treatment challenging. In the present study, Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to discriminate the pathological regions of patient-derived biopsies of parotid neoplasms by metabolomic and lipidomic profiles. Fresh frozen parotid tissues were analyzed by MALDI time-of-flight (TOF) MSI, both in positive and negative ionization modes, and additional MALDI-Fourier-transform ion cyclotron resonance (FT-ICR) MSI was carried out for metabolite annotation. MALDI-TOF-MSI spatial segmentation maps with different molecular signatures were compared with the histologic annotation. To maximize the information related to specific alterations between the pathological and healthy tissues, unsupervised (principal component analysis, PCA) and supervised (partial least squares-discriminant analysis, PLS-DA) multivariate analyses were performed presenting a 95.00% accuracy in cross-validation. Glycerophospholipids significantly increased in tumor tissues, while sphingomyelins and triacylglycerols, key players in the signaling pathway and energy production, were sensibly reduced. In addition, a significant increase of amino acids and nucleotide intermediates, consistent with the bioenergetics request of tumor cells, was observed. These results underline the potential of MALDI-MSI as a complementary diagnostic tool to improve the specificity of diagnosis and monitoring of pharmacological therapies.

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Section: Metabolome Differences Between Tumor and Non-tumor Areas Of ...supporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

MALDI Mass Spectrometry Imaging Highlights Specific Metabolome and Lipidome Profiles in Salivary Gland Tumor Tissues

et al. 2022

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“…For mitochondria staining [ 57 ], after the treatment, the medium was removed; thus, the cells seeded on glass coverslips were incubated for 30 min at 37 °C in a serum-free medium containing 200 nM Mitotracker Red CMXRos (Invitrogen-Molecular Probes, Waltham, MA, USA). Coverslips were fixed in PBS-4% paraformaldehyde, and then permeabilized in cold acetone for 5 min on ice.…”

Section: Methodsmentioning

confidence: 99%

Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK

et al. 2022

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Parkinson’s disease (PD) represents one of the most common neurodegenerative disorders, characterized by a dopamine (DA) deficiency in striatal synapses and misfolded toxic α-synuclein aggregates with concomitant cytotoxicity. In this regard, the misfolded proteins accumulation in neurodegenerative disorders induces a remarkable perturbations of endoplasmic reticulum (ER) homeostasis leading to persistent ER stress, which in turn, effects protein synthesis, modification, and folding quality control. A large body of evidence suggests that natural products target the ER stress signaling pathway, exerting a potential action in cancers, diabetes, cardiovascular and neurodegenerative diseases. This study aims to assess the neuroprotective effect of cocoa extract and its purified fractions against a cellular model of Parkinson’s disease represented by 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma. Our findings demonstrate, for the first time, the ability of cocoa to specifically targets PERK sensor, with significant antioxidant and antiapoptotic activities as both crude and fractioning extracts. In addition, cocoa also showed antiapoptotic properties in 3D cell model and a notable ability to inhibit the accumulation of α-synuclein in 6-OHDA-induced cells. Overall, these results indicate that cocoa exerts neuroprotective effects suggesting a novel possible strategy to prevent or, at least, mitigate neurodegenerative disorders, such as PD.

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“…During the last several decades, a plethora of different thiazolidine based compounds have been studied to evaluate their pharmacological potential [ 1 , 2 ]. The synthesis of thiazole derivatives has attracted widespread attention due to their diverse biological activities, including antimicrobial [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ], anti-inflammatory [ 10 , 11 , 12 ], analgesic [ 13 , 14 ], antitumor [ 15 , 16 , 17 ], antidiabetic [ 18 ], anti-HIV [ 19 , 20 ], COX/LOX inhibitory [ 21 , 22 ], antioxidant [ 23 , 24 ], antileishmanial [ 25 , 26 ], and many others [ 27 , 28 , 29 , 30 ]. There are many drugs with this scaffold such as antitumor (dasatinib, tiazofurin,); antiviral (brecanavir, ritonavir); anti-infectious (nitazoxanide) [ 31 ]; antibacterial agents, including sulfathiazole [ 32 ] and penicillins [ 33 ]; and antifungal agents, such as ravuconazole [ 34 ], myxothiazol [ 35 ], abafungin [ 36 ], and ethaboxam [ 37 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimicrobial Activity of New Heteroaryl(aryl) Thiazole Derivatives Molecular Docking Studies

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Herein, we report the design, synthesis, and evaluation of the antimicrobial activity of new heteroaryl (aryl) thiazole derivatives. The design was based on a molecular hybridization approach. The in vitro evaluation revealed that these compounds demonstrated moderate antibacterial activity. The best activity was achieved for compound 3, with MIC and MBC in the range of 0.23–0.7 and 0.47–0.94 mg/mL, respectively. Three compounds (2, 3, and 4) were tested against three resistant strains, namely methicillin resistant Staphylococcus aureus, P. aeruginosa, and E. coli, which showed higher potential than the reference drug ampicillin. Antifungal activity of the compounds was better with MIC and MFC in the range of 0.06–0.47 and 0.11–0.94 mg/mL, respectively. The best activity was observed for compound 9, with MIC at 0.06–0.23 mg/mL and MFC at 0.11–0.47 mg/mL. According to docking studies, the predicted inhibition of the E. coli MurB enzyme is a putative mechanism of the antibacterial activity of the compounds, while inhibition of 14a-lanosterol demethylase is probably the mechanism of their antifungal activity.

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Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification

Cited by 33 publications

References 55 publications

MALDI Mass Spectrometry Imaging Highlights Specific Metabolome and Lipidome Profiles in Salivary Gland Tumor Tissues

MALDI Mass Spectrometry Imaging Highlights Specific Metabolome and Lipidome Profiles in Salivary Gland Tumor Tissues

Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK

Synthesis and Antimicrobial Activity of New Heteroaryl(aryl) Thiazole Derivatives Molecular Docking Studies

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