Relevant bibliographies by topics / Choline Kinase Inhibitor

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Academic literature on the topic 'Choline Kinase Inhibitor'

Author: Grafiati
Published: 9 March 2023

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Journal articles on the topic "Choline Kinase Inhibitor"

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Wieprecht, M., T. Wieder, and C. C. Geilen. "N-[2-bromocinnamyl(amino)ethyl]-5-isoquinolinesulphonamide (H-89) inhibits incorporation of choline into phosphatidylcholine via inhibition of choline kinase and has no effect on the phosphorylation of CTP:phosphocholine cytidylyltransferase." Biochemical Journal 297, no. 1 (January 1, 1994): 241–47. http://dx.doi.org/10.1042/bj2970241.

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We have shown previously that N-[2-bromocinnamyl(amino)-ethyl]-5-isoquinolinesulphonamide (H-89), a selective inhibitor of cyclic-AMP-dependent protein kinase (PKA), inhibits phosphatidylcholine biosynthesis in HeLa cells. In the present study, we elucidated the mechanism underlying the described inhibition. Treatment of cells with 10 microM H-89 had no effect on the phosphorylation of CTP:phosphocholine cytidylyltransferase. However, H-89 slightly affected the distribution of cytidylyltransferase between cytosol and membranes, but the cellular 1,2-diacylglycerol content was not influenced. Furthermore, pulse-chase experiments revealed that H-89 did not affect cytidylyltransferase activity. Instead, H-89 inhibited choline kinase, the enzyme catalysing the first step in the CDP-choline pathway. In the presence of 10 microM H-89, choline kinase activity was inhibited by 36 +/- 7.6% in vitro. Additionally, the phosphorylation of choline to phosphocholine was inhibited by 30 +/- 3% in cell-culture experiments. This inhibitory effect could be partly prevented by simultaneous addition of 10 microM forskolin, indicating that choline kinase is regulated in part by PKA activity.
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Zimmerman, Tahl, Juan Carlos Lacal, and Salam A. Ibrahim. "A dual choline/phosphocholine colorimetric method for measuring the relative strength of inhibitors of choline kinases of Gram-positive pathogens." Food Science and Applied Biotechnology 1, no. 2 (October 10, 2018): 131. http://dx.doi.org/10.30721/fsab2018.v1.i2.40.

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Using chemical and artificial preservation methods to keep food safe is becoming an issue with consumers. Therefore, it is important to discover antimicrobials from natural sources for use in food safety applications. The objective of the present study was to establish screening system for natural inhibitors of choline kinase (ChoK), a known antimicrobial target. A previously developed dual choline/phosphocholine colorimetric method was used to determine the relative strength of 3 choline kinase inhibitors: Hemocholinium-3, RSM-928A, and MN58 . Whole cell extracts containing the choline kinase of Streptococcus pneumoniae (sChoK) was used as a model. The measured IC50 values of these drugs were >2700 µM, 0.54 µM, and 170-225 µM, respectively. Importantly, not every step of the colorimetric method could be used in the case of every inhibitor, since each had its own particular reactive profile with the colorimetric dyes, which could have lead to confounded measurements. However, in every case, the system was flexible enough to measure choline or phosphocholine, if not both metabolites. We establish here that this dual choline/phosphocholine system is flexible enough to measure the IC50 any possible inhibitor. This colorimetric method is an ideal benchtop method for screening for natural inhibitors of bacterial ChoKs.
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Miwa, Masaichi, Atsushi Suzuki, Yasuko Watanabe, Junji Shinoda, Yutaka Oiso, and Osamu Kozawa. "Vasopressin activates phospholipase D through pertussis toxin-insensitive GTP-binding protein in aortic smooth muscle cells: function of Ca2+/calmodulin." Biochemistry and Cell Biology 73, no. 3-4 (March 1, 1995): 191–99. http://dx.doi.org/10.1139/o95-023.

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In the present study, we examined the effect of vasopressin (AVP) on phosphatidylcholine-hydrolyzing phospholipase D activity in primary cultured rat aortic smooth muscle cells. AVP stimulation of choline formation was dose dependent. The time-course was quite different from those of inositol phosphates. The effect of AVP on the formation of inositol phosphates (EC50 was 3 nM) was more potent than that on the formation of choline (EC50 was 30 nM). 12-O-Tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C (PKC), stimulated the formation of choline. However, 4α-phorbol 12,13-didecanoate, which is inactive for PKC, had little effect. Staurosporine, an inhibitor of protein kinases, which inhibited the TPA-induced formation of choline, had little effect on the AVP-induced formation of choline. Neither calphostin C, a highly specific PKC inhibitor, nor PKC down-regulation with TPA affected AVP-induced formation of choline. A combination of AVP and TPA additively stimulated the formation of choline. The depletion of extracellular Ca2+ by (ethylenebis(oxyethylenenitrilo))tetraacetic acid significantly reduced the AVP-induced formation of choline. W-7, an antagonist of calmodulin, inhibited the AVP-induced formation of choline in a dose-dependent manner. NaF, an activator for GTP-binding protein (G-protein), stimulated the formation of choline. However, the formation of choline by a combination of AVP and NaF was not additive. Pertussis toxin had little effect on the AVP-induced formation of choline. These results strongly suggest that AVP stimulates phospholipase D in a Ca2+/calmodulin-dependent manner in aortic smooth muscle cells, that a pertussis-toxin-insensitive G-protein is involved in the AVP-induced phospholipase D activation, and furthermore, that PKC is not essential for the activation.Key words: vasopressin, phospholipase D, protein kinase C, calmodulin, GTP-binding protein, aortic smooth muscle cells.
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Zimmerman, Tahl, and Salam A. Ibrahim. "Quercetin Is a Novel Inhibitor of the Choline Kinase of Streptococcus pneumoniae." Antibiotics 11, no. 9 (September 19, 2022): 1272. http://dx.doi.org/10.3390/antibiotics11091272.

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The effectiveness of current antimicrobial methods for addressing for food-borne Gram-positive pathogens has dropped with the emergence of resistant strains. Consequently, new methods for addressing Gram-positive strains have to be developed continuously. This includes establishing novel targets for antimicrobial discovery efforts. Eukaryotic choline kinases have been highly developed as drug targets for the treatment of cancer, rheumatoid arthritis, malaria and many other conditions and diseases. Recently, choline kinase (ChoK) has been proposed as a drug target for Gram-positive species generally. The aim of this work was to discover novel, natural sources of inhibitors for bacterial ChoK from tea extracts. We report the first natural bacterial ChoK inhibitor with antimicrobial activity against Streptococcus pneumoniae: quercetin.
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Shinoda, J., A. Suzuki, Y. Oiso, and O. Kozawa. "Thromboxane A2-stimulated phospholipase D in osteoblast-like cells: possible involvement of PKC." American Journal of Physiology-Endocrinology and Metabolism 269, no. 3 (September 1, 1995): E524—E529. http://dx.doi.org/10.1152/ajpendo.1995.269.3.e524.

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We examined the effect of thromboxane A2 (TxA2) on phosphatidylcholine-hydrolyzing phospholipase D activity in osteoblast-like MC3T3-E1 cells. 9,11-Epithio-11,12-methanothromboxane A2 (STA2), a stable analogue of TxA2, stimulated the formations of both choline and inositol phosphates in a dose-dependent manner in the range between 10 nM and 10 microM. The formation of choline stimulated by a combination of STA2 and 12-O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C-activating phorbol ester, was not additive. 1-(5-Isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7), an inhibitor of protein kinases, suppressed the formation of choline induced by STA2 as well as that by TPA, but 20 microM N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), a control for H-7 as a protein kinase C inhibitor, had little effect. Calphostin C, a potent and specific inhibitor of protein kinase C, also suppressed the formation of choline induced by STA2. The STA2-induced formation of choline was significantly reduced by chelating extracellular Ca2+ with ethylene glycol-bis(beta-amino-ethyl ether)-N,N,N',N'-tetraacetic acid. STA2 dose dependently stimulated 45Ca2+ influx from extracellular space. STA2 stimulated DNA synthesis of MC3T3-E1 cells and increased the number of these cells. These results suggest that TxA2 stimulates phospholipase D in osteoblast-like cells, resulting in the direction of their proliferation, and that the activation of protein kinase C is involved in the stimulation of phospholipase D.
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Khalifa, Moad, Ling Ling Few, and Wei Cun See Too. "Phage-choline Kinase Inhibitor Combination to Control Pseudomonas aeruginosa: A Promising Combo." Mini-Reviews in Medicinal Chemistry 22, no. 9 (May 2022): 1281–88. http://dx.doi.org/10.2174/1389557521666211213160256.

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Background:: Pseudomonas aeruginosa is one of the most prevalent opportunistic pathogens in humans that has thrived and proved to be difficult to control in this “post-antibiotic era.” Antibiotic alternatives are necessary for fighting against this resilient bacterium. Even though phages might not be “the wonder drug” that solves everything, they still provide a viable option to combat P. aeruginosa and curb the threat it imposes. Main findings:: The combination of antibiotics with phages, however, poses a propitious treatment option for P. aeruginosa. Choline kinase (ChoK) is the enzyme that synthesizes phosphorylcholine subsequently incorporated into lipopolysaccharide located at the outer membrane of gram-negative bacteria. Recently, inhibition of ChoKs has been proposed as a promising antibacterial strategy. Successful docking of Hemicholinium-3, a choline kinase inhibitor, to the model structure of P. aeruginosa ChoK also supports the use of this inhibitor or its derivatives to inhibit the growth of this microorganism. Conclusion:: Therefore, the combination of the novel antimicrobial “choline kinase inhibitors (ChoKIs)” with a phage cocktail or synthetic phages as a potential treatment for P. aeruginosa infection has been proposed.
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Choubey, Vinay, Pallab Maity, Mithu Guha, Sanjay Kumar, Kumkum Srivastava, Sunil Kumar Puri, and Uday Bandyopadhyay. "Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism." Antimicrobial Agents and Chemotherapy 51, no. 2 (December 4, 2006): 696–706. http://dx.doi.org/10.1128/aac.00919-06.

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ABSTRACT Choline kinase is the first enzyme in the Kennedy pathway (CDP-choline pathway) for the biosynthesis of the most essential phospholipid, phosphatidylcholine, in Plasmodium falciparum. In addition, choline kinase also plays a pivotal role in trapping essential polar head group choline inside the malaria parasite. Recently, Plasmodium falciparum choline kinase (PfCK) has been cloned, overexpressed, and purified. However, the function of this enzyme in parasite growth and survival has not been evaluated owing to the lack of a suitable inhibitor. Purified recombinant PfCK enabled us to identify an inhibitor of PfCK, hexadecyltrimethylammonium bromide (HDTAB), which has a very close structural resemblance to hexadecylphosphocholine (miltefosin), the well-known antiproliferative and antileishmanial drug. HDTAB inhibited PfCK in a dose-dependent manner and offered very potent antimalarial activity in vitro against Plasmodium falciparum. Moreover, HDTAB exhibited profound antimalarial activity in vivo against the rodent malaria parasite Plasmodium yoelii (N-67 strain). Interestingly, parasites at the trophozoite and schizont stages were found to be particularly sensitive to HDTAB. The stage-specific antimalarial effect of HDTAB correlated well with the expression pattern of PfCK in P. falciparum, which was observed by reverse transcription-PCR and immunofluorescence microscopy. Furthermore, the antimalarial activity of HDTAB paralleled the decrease in phosphatidylcholine content, which was found to correlate with the decreased phosphocholine generation. These results suggest that inhibition of choline kinase by HDTAB leads to decreased phosphocholine, which in turn causes a decrease in phosphatidylcholine biosynthesis, resulting in death of the parasite.
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Jabalera, Ylenia, Alberto Sola-Leyva, Ana Peigneux, Federica Vurro, Guillermo R. Iglesias, Jesus Vilchez-Garcia, Inmaculada Pérez-Prieto, et al. "Biomimetic Magnetic Nanocarriers Drive Choline Kinase Alpha Inhibitor inside Cancer Cells for Combined Chemo-Hyperthermia Therapy." Pharmaceutics 11, no. 8 (August 12, 2019): 408. http://dx.doi.org/10.3390/pharmaceutics11080408.

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Choline kinase α1 (ChoKα1) has become an excellent antitumor target. Among all the inhibitors synthetized, the new compound Ff35 shows an excellent capacity to inhibit ChoKα1 activity. However, soluble Ff35 is also capable of inhibiting choline uptake, making the inhibitor not selective for ChoKα1. In this study, we designed a new protocol with the aim of disentangling whether the Ff35 biological action is due to the inhibition of the enzyme and/or to the choline uptake. Moreover, we offer an alternative to avoid the inhibition of choline uptake caused by Ff35, since the coupling of Ff35 to novel biomimetic magnetic nanoparticles (BMNPs) allows it to enter the cell through endocytosis without interacting with the choline transporter. This opens the possibility of a clinical use of Ff35. Our results indicate that Ff35-BMNPs nanoassemblies increase the selectivity of Ff35 and have an antiproliferative effect. Also, we demonstrate the effectiveness of the tandem Ff35-BMNPs and hyperthermia.
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Guma, M., E. Sanchez-Lopez, A. Lodi, R. Garcia-Carbonell, S. Tiziani, M. Karin, J. C. Lacal, and G. S. Firestein. "Choline kinase inhibition in rheumatoid arthritis." Annals of the Rheumatic Diseases 74, no. 7 (October 1, 2014): 1399–407. http://dx.doi.org/10.1136/annrheumdis-2014-205696.

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ObjectivesLittle is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKα), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage.MethodsCholine metabolic profile of FLS cells was determined by 1H magnetic resonance spectroscopy (1HMRS) under conditions of ChoKα inhibition. FLS function was evaluated using the ChoKα inhibitor MN58b (IC50=4.2 μM). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration.ResultsThe enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKα expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoKα inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoKα inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease.ConclusionsThese data suggest that ChoKα inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions.
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Yasui, K., M. Yamazaki, M. Miyabayashi, T. Tsuno, and A. Komiyama. "Signal transduction pathway in human polymorphonuclear leukocytes for chemotaxis induced by a chemotactic factor. Distinct from the pathway for superoxide anion production." Journal of Immunology 152, no. 12 (June 15, 1994): 5922–29. http://dx.doi.org/10.4049/jimmunol.152.12.5922.

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Abstract The tyrosine kinase inhibitors erbstatin and herbimycin A inhibited the chemotactic response to FMLP (2 x 10(-7) M) and the superoxide anion (O2-) production stimulated by FMLP (1 x 10(-6) M) in human polymorphonuclear leukocytes (PMN) in similar manners. These compounds also inhibited phospholipase D (PLD)-catalyzed breakdown of phosphatidyl choline, suggesting a possible link between tyrosine kinase and PLD. In the presence of propranolol (phosphatidic acid (PA) phosphohydrolase inhibitor), or ethanol, the activation of PLD results in the modulation of PA and/or diglyceride (DG) generation, producing an irregularity in O2- production. However, PMN motility was not affected in these conditions. These results suggest that PLD is a downstream effector of FMLP-induced tyrosine kinase activation that leads to activation of the PMN superoxide release but not to chemotactic migration. In contrast, the tyrosine kinase inhibitors did not inhibit inositol 1,4,5-triphosphate generation and increase of intracellular concentration of free calcium. Furthermore, a protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), did not affect the migration of PMN and the activation of PLD induced by FMLP at concentrations of less than 50 microM. These results support the premise that there is a specific signaling pathway for chemoattractant-induced PMN locomotion.
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Dissertations / Theses on the topic "Choline Kinase Inhibitor"

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Mariotto, Elena. "In vitro and in vivo antitumor activity of new choline kinase inhibitor: a pharmacological strategy for breast cancer and leukemia treatment." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3423255.

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Aberrant choline metabolism is a feature shared by many tumors. It is predominantly caused by elevated expression and activation of choline kinase alpha (ChoKα), which catalyzes the phosphorylation of choline to phosphocholine in the Kennedy’s pathway for membrane lipids synthesis. In this PhD thesis, the most promising symmetrical ChoKα inhibitor has been identified from the novel series of choline kinase inhibitors, designed and synthesized by Prof. Lopez-Cara’s group, University of Granada, Spain. The therapeutic potential of the selected lead compound was compared to previously reported symmetrical ChoKα inhibitors and evaluated in two different tumoral contexts. Furthermore, the new ChoKα inhibitor was used to investigate for the first time choline metabolism deregulation in hematological tumors. The ChoKα inhibitor EB-3D (also known as compound 10a) was selected as lead compound. The crystal structure of ChoKα1 in complex with compound EB-3D (PDB ID: 5FTG) reveals that the compound effectively binds to the choline-binding site and inhibits ChoKα1 with IC50 of 1.00 ± 0.01 μM. EB-3D strongly inhibits cell growth in a panel of cancer cell lines with GI50 ranging from 27 to 110 nM for solid tumors and from 0.9 to 479 nM for hematological tumors. EB-3D inhibits also the formation of phosphocholine and reduces the content of choline-containg metabolites in treated cells. In triple-negative MDA-MB-231 breast cancer cells, EB-3D arrests cells in the G0/G1 phase of the cell cycle triggering irreversible cellular senescence. Moreover, EB-3D potentiates the antitumoral effect of cisplatin and impairs migration and invasiveness of the higly metastatic MDA-MB-231 cell line. Lastly, treatment of syngeneic orthotopic EO771- C57BL/6 mouse model with 1mg/kg of EB-3D i.p. resulted in strong tumour growth inhibition and reduction of metastasis formation. Alltogether, these data reveal the antitumorigenic and antimetastatic potential of EB-3D in triple-negative breast cancer (TNBC). T acute lymphoblastic leukemia (T-ALL) cell lines exhibit increased levels of ChoKα compared to healthy lymphocytes and higher ChoKα/β ratio. EB-3D induces G0/G1 cell cycle arrest in T-ALL and, in contrast to breast cancer cells, induces cell death by apoptosis. The effect is rapidly triggered and cannot be rescued by compound withdrawal. EB-3D modulates the AMPK-mTOR pathway leading to the inactivation of final effectors required for protein synthesis and cell cycle progression. On the contrary, the effect appears attenuated in normal lymphocytes where other signaling pathways are involved. Finally, EB-3D strongly synergizes with L-asparaginase lowering the GI50 and increasing cell death. Taken together, these data validate ChoKα as a novel attractive therapeutic target in T-ALL and justify the further development of EB-3D inhibitor.
L’enzima colina chinasi α (ChoKα) catalizza la fosforilazione della colina in fosfocolina nel primo step del Kennedy pathway che porta alla biosintesi dei fosfolipidi di membrana. Negli ultimi anni l’overespressione e/o iperattivazione dell’enzima ChoKα sono state descritte in diverse neoplasie, dove correlano con una peggior prognosi oltre che ad un’aumentata invasività e resistenza alle comuni terapie oncologiche. Dunque, per la sua rilevanza in campo oncologico, quest’enzima è recentemente diventato oggetto di interesse per lo sviluppo di inibitori selettivi. In questa tesi di Dottorato viene identificato l’inibitore simmetrico di ChoKα più promettente all’interno di una serie di nuovi composti disegnati e sintetizzati dal gruppo della Prof.ssa Lopez-Cara dell’Università di Granada, Spagna. Il potenziale terapeutico del composto selezionato è stato comparato con i due inibitori simmetrici di ChoKα di riferimento descritti in letteratura e valutato in due diversi contesti tumorali. Inoltre, il nuovo inibitore di ChoKα è stato usato per descrivere per la prima volta l’alterato metabolismo della colina nei tumori ematologici. Il composto EB-3D (riportato anche con il nome di composto 10a) è stato selezionato come migliore inibitore simmetrico di ChoKα. La struttura cristallografica di EB-3D in complesso con l’isoforma ChoKα1 (PDB ID: 5FTG) rivela che il composto si colloca nella tasca contenente il sito di legame della colina inibendo così ChoKα1 con IC50 di 1.00 ± 0.01 μM. EB-3D riduce drasticamente la proliferazione cellulare in un pannello di linee tumorali con GI50 che variano da 27 a 110 nM per i tumori solidi e da 0.9 a 479 nM per i tumori ematologici. EB-3D inoltre inibisce la formazione di fosfocolina e, in generale, riduce la quantità dei composti contenenti colina nelle cellule trattate. Nella linea cellulare di tumore mammario triplo negativo MDA-MB-231, EB-3D induce un blocco del ciclo cellulare nella fase G0/G1 innescando il processo della senescenza cellulare. EB-3D inoltre potenzia l’effetto antitumorale del cisplatino e interferisce sia sulla migrazione che sull’invasione di questa linea cellulare altamente metastatica. Infine, la somministrazione per via intraperitoneale di EB-3D nel modello murino singenico ortotopico EO771-C57BL/6 ha portato ad una significativa riduzione della massa tumorale e alla riduzione della formazione di metastasi polmonari. Complessivamente, questi dati rivelano il potenziale antitumorale e antimetastastico del nuovo inibitore di ChoKα EB-3D nella forma più aggressive di tumore al seno. Parallelamente, in questa tesi viene descritto per la prima volta che diverse linee cellulari di leucemia linfoblastica acuta di tipo T (T-ALL) esibiscono elevati livelli di ChoKα rispetto ai linfociti sani. EB-3D induce anche in questo caso l’arresto del ciclo cellulare in fase G0/G1 e, contrariamente a quanto osservato nelle cellule di tumore mammario, innesca l’apoptosi in modo rapido e irreversibile. EB-3D modula inoltre il pathway di AMPK-mTOR portando all’inattivazione degli effettori finali coinvolti nella sintesi proteica e nella progressione del ciclo cellulare. Infine, EB-3D sinergizza con L-asparaginasi, con incremento dell’apoptosi cellulare. Concludendo, questi risultati dimostrano che ChoKα può essere considerato un nuovo target terapeutico per le leucemie acute linfoblastiche e giustificano l’ulteriore sviluppo dell’inibitore EB-3D.
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Trousil, Sebastian. "Choline kinase inhibition as a treatment strategy of cancers with deregulated lipid metabolism." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/25146.

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Aberrant choline metabolism is a characteristic shared by many human cancers. It is predominantly caused by elevated expression of choline kinase alpha, which catalyses the phosphorylation of choline to phosphocholine, an essential precursor of membrane lipids. In this thesis, a novel choline kinase inhibitor has been developed and its therapeutic potential evaluated. Furthermore the probe was used to elaborate choline kinase biology. A lead compound, ICL-CCIC-0019 (IC50 of 0.27 ± 0.06 μM), was identified through a focused library screen. ICL-CCIC-0019 was competitive with choline and non-competitive with ATP. In a selectivity screen of 131 human kinases, ICL-CCIC-0019 inhibited only 5 kinases more than 20% at a concentration of 10 μM (< 35% in all 131 kinases). ICL- CCIC-0019 potently inhibited cell growth in a panel of 60 cancer cell lines (NCI-60 screen) with a median GI50 of 1.12 μM (range: 0.00389-16.2 μM). Importantly, proliferation of normal cells was only minimally affected (MCF-10A, ST-T1b and CCD-18Co; GI50 30-120 μM). In HCT116 cells, ICL-CCIC-0019 potently inhibited the formation of phosphocholine (EC50 0.67 ± 0.28 μM), which consequently decreased the formation of phosphatidylcholine. The compound arrested cells in the G1 phase of the cell cycle, and induced endoplasmic reticulum stress and apoptosis. A single injection of ICL-CCIC-0019 at 10 mg/kg decreased tumour uptake of the choline kinase specific PET tracer [18F]fluoromethyl-[1,2-2H4]-choline at 24 hours (AUC0-60-23%). Treatment of HCT116 colon cancer cell xenograft bearing mice with 5 mg/kg ICL-CCIC-0019 i.p. resulted in strong tumour growth inhibition. Human breast cancer cell lines oncogenically transformed by HER2 exhibit increased levels of phosphocholine and are therefore more likely respond to CHKA inhibition. To identify such patients more readily, a novel, non-invasive, PET-imaging-based HER2- targeting diagnostic tool, [18F]GE-226, was developed. [18F]GE-226 (KD = 76 pM) uptake was 11 to 67-fold higher in 10 HER2 positive versus negative cell lines in vitro. Tumour uptake correlated with HER2 expression in 5 different tumour models (r2 = 0.78), and a fluorophore-labelled tracer analogue co-localised with HER2 expression. Tracer uptake was not influenced by short-term or continuous treatment with trastuzumab, but reflected HER2 degradation by short-term HSP90 inhibition. Taken together, these data further validate CHKA as a drug target and warrant the further development of ICL-CCIC-0019, potentially in the setting of HER2 positive cancers.
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Books on the topic "Choline Kinase Inhibitor"

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Takao, Kumazawa, Kruger Lawrence, and Mizumura Kazue, eds. The polymodal receptor: A gateway to pathological pain. Amsterdam: Elsevier, 1996.

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(Editor), T. Kumazawa, L. Kruger (Editor), and K. Mizumura (Editor), eds. The Polymodal Receptor - A Gateway to Pathological Pain (Progress in Brain Research). Elsevier Science, 1996.

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Conference papers on the topic "Choline Kinase Inhibitor"

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Trousil, Sebastian, Maciej Kalisczcak, Zachary Schug, Quang-De Nguyen, Giampaolo Tomasi, Rosy Favicchio, Diana Brickute, et al. "Abstract C118: Choline kinase inhibition with the novel pharmacological inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-c118.

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Mariotto, Elena, Roberta Bortolozzi, Roberto Ronca, Luisa C. López-Cara, Benedetta Accordi, Valentina Serafin, Giuseppe Basso, and Giampietro Viola. "Abstract 1233:In vitroandin vivopharmacological study of EB-3D: a novel choline kinase inhibitor for breast cancer treatment." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-1233.

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Gnocchi, Paola, Francesca Quartieri, Alessandra Badari, Roberta Bosotti, Elena Casale, Emiliana Corti, Cinzia G. Cristiani, et al. "Abstract 4790: Identification and characterization of ATP-mimetic choline kinase inhibitors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4790.

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Gnocchi, Paola, Francesca Quartieri, Alessandra Badari, Roberta Bosotti, Elena Casale, Emiliana Corti, Cinzia G. Cristiani, et al. "Abstract 4790: Identification and characterization of ATP-mimetic choline kinase inhibitors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4790.

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Sanchez-Lopez, Elsa, Laura Menchén, Esther Seco, Teresa Gómez del Pulgar, Juan Carlos Lacal, and Arancha Cebrián. "Abstract 2644: Inhibition of choline kinase increases endoplasmic reticulum stress proteins." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2644.

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Squillace, Rachel M., Stephan Zech, Feng Li, Anna Kohlmann, David Miller, Matthew Greenfield, Yaoyu Ning, et al. "Abstract 3236: Small molecule inhibitors of choline kinase lead to reduced phosphocholine levels and induction of apoptosis in cancer cells." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-3236.

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Zhu, Mingming, Harlan E. Shannon, Melissa Trowbridge, Michael D. Cockman, Emily C. Rothstein, Sandaruwan Geeganage, and Anthony S. Fischl. "Abstract B117: Early detection of a metabolic tumor response to p70S6 kinase/AKT inhibition by LYS6KAKT1 using in vivo choline proton magnetic resonance spectroscopy." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-b117.

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