choline uptake
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2022 ◽  
Vol 47 (2) ◽  
pp. 101-107
Author(s):  
Virginia Liberini ◽  
Gregoire B. Morand ◽  
Niels J. Rupp ◽  
Erika Orita ◽  
Désirée Deandreis ◽  
...  

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 329
Author(s):  
Kaoru Shibata ◽  
Nozomi Nishijima ◽  
Kaho Hirai ◽  
Saiichiro Watanabe ◽  
Tsuyoshi Yamanaka ◽  
...  

Background: Despite recent advances in the early detection and treatment of TSCC patients, recurrence rates and survival rates have not improved. The high frequency of lymph node metastasis is one of the causes, and the drug development of new therapeutic mechanisms such as metastasis control is desired. Choline transporter-like protein 1 (CTL1) has attracted attention as a target molecule in cancer therapy. In this study, we examined the antitumor effects of Amb544925, a plant-derived CTL1 inhibitor. Methods: The TSCC cell line HSC-3 was used to measure [3H]choline uptake, cell survival, caspase activity, and cell migration. Xenograft model mice were prepared to verify the antitumor effect of Amb544925. Results: Amb544925 inhibited cell viability and increased caspase-3/7 activity at concentrations that inhibited choline uptake. Amb544925 and ceramide increased SMPD4 expression and suppressed surivivin expression. Furthermore, Amb544925 and ceramide inhibited the migration of HSC-3 cells. In the xenograft model mice, Amb544925 suppressed tumor growth and CTL1 mRNA expression. Conclusions: The plant-derived CTL1 inhibitor Amb544925 is a lead compound of a new anticancer agent exhibiting antitumor effects and inhibition of cell migration through the ceramide/survivin pathway.


2021 ◽  
Vol 14 ◽  
Author(s):  
Nicoletta Urbano ◽  
Manuel Scimeca ◽  
Elena Bonanno ◽  
Orazio Schillaci

Background: The development of less expensive and pivotal methodologies, capable to support the researchers in the radiopharmaceutical pre-clinical investigations could provide a crucial incentive for developing biomedical research involved in the realization of tailored target therapies. Objective: The aim of this pilot study was to evaluate the capability of a digital autoradiography system equipped with a laser scanning device to perform [18F]choline biodistribution evaluation in a xenograft mouse model of prostate cancer. Methods: PC3 prostate cancer cells were used to develop xenografts in NOD/SCID mice. The biodistribution of the radiopharmaceutical was evaluated at 30,60 and 120 min after injection in excised organs by using a digital autoradiography system equipped with super resolution laser screen. Histological and immunohistochemical analysis were performed to correlate the [18F]choline uptake with morphological and molecular tumours characteristics. Results: Data here reported clearly indicate the possibility to perform accurate biodistribution studies by using the digital autoradiographic system equipped with a super resolution screen. Specifically, a significant increase in the [18F]choline inhibitor uptake in PC3 tumours as compared to heart, bowel, liver and kidney at both 30 and 60 min was observed. More important, the digital autoradiographic system showed signal uptake almost exclusively in the PC3 tumors at 60 min post-injection. Noteworthy, immunohistochemical analysis demonstrated a strong overlapping between the [18F]choline uptake and the proliferation index (Ki67 expression). Conclusions: The use of autoradiography system in pre-clinical investigations could shed new light on the molecular mechanisms that orchestrate the tissues damage induced by therapeutical radiopharmaceuticals.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1842
Author(s):  
Francisco José Aguilar-Troyano ◽  
Archimede Torretta ◽  
Gianluca Rubbini ◽  
Alberto Fasiolo ◽  
Pilar María Luque-Navarro ◽  
...  

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1360
Author(s):  
Santiago Schiaffino-Ortega ◽  
Elena Mariotto ◽  
Pilar María Luque-Navarro ◽  
María Kimatrai-Salvador ◽  
Pablo Rios-Marco ◽  
...  

Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.


2021 ◽  
Vol 22 (16) ◽  
pp. 8857
Author(s):  
Samantha D. Francis Stuart ◽  
Alice R. Villalobos

Choroid plexus (CP) sequesters cadmium and other metals, protecting the brain from these neurotoxins. These metals can induce cellular stress and modulate homeostatic functions of CP, such as solute transport. We previously showed in primary cultured neonatal rat CP epithelial cells (CPECs) that cadmium induced cellular stress and stimulated choline uptake at the apical membrane, which interfaces with cerebrospinal fluid in situ. Here, in CPECs, we characterized the roles of glutathione (GSH) and Zinx supplementation in the adaptive stress response to cadmium. Cadmium increased GSH and decreased the reduced GSH-to-oxidized GSH (GSSG) ratio. Heat shock protein-70 (Hsp70), heme oxygenase (HO-1), and metallothionein (Mt-1) were induced along with the catalytic and modifier subunits of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH synthesis. Inhibition of GCL by l-buthionine sulfoximine (BSO) enhanced stress protein induction and stimulation of choline uptake by cadmium. Zinx alone did not induce Hsp70, HO-1, or GCL subunits, or modulate choline uptake. Zinx supplementation during cadmium exposure attenuated stress protein induction and stimulation of choline uptake; this effect persisted despite inhibition of GSH synthesis. These data indicated up-regulation of GSH synthesis promotes adaptation to cadmium-induced cellular stress in CP, but Zinx may confer cytoprotection independent of GSH.


Nanomaterials ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2057
Author(s):  
Ricardo J. B. Pinto ◽  
Nicole S. Lameirinhas ◽  
Gabriela Guedes ◽  
Gustavo H. Rodrigues da Silva ◽  
Párástu Oskoei ◽  
...  

Cellulose nanocrystals (CNCs) are elongated biobased nanostructures with unique characteristics that can be explored as nanosystems in cancer treatment. Herein, the synthesis, characterization, and cellular uptake on folate receptor (FR)-positive breast cancer cells of nanosystems based on CNCs and a chitosan (CS) derivative are investigated. The physical adsorption of the CS derivative, containing a targeting ligand (folic acid, FA) and an imaging agent (fluorescein isothiocyanate, FITC), on the surface of the CNCs was studied as an eco-friendly methodology to functionalize CNCs. The fluorescent CNCs/FA-CS-FITC nanosystems with a rod-like morphology showed good stability in simulated physiological and non-physiological conditions and non-cytotoxicity towards MDA-MB-231 breast cancer cells. These functionalized CNCs presented a concentration-dependent cellular internalization with a 5-fold increase in the fluorescence intensity for the nanosystem with the higher FA content. Furthermore, the exometabolic profile of the MDA-MB-231 cells exposed to the CNCs/FA-CS-FITC nanosystems disclosed a moderate impact on the cells’ metabolic activity, limited to decreased choline uptake and increased acetate release, which implies an anti-proliferative effect. The overall results demonstrate that the CNCs/FA-CS-FITC nanosystems, prepared by an eco-friendly approach, have a high affinity towards FR-positive cancer cells and thus might be applied as nanocarriers with imaging properties for active targeted therapy.


Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4034
Author(s):  
Andor Veltien ◽  
Jack van Asten ◽  
Niveditha Ravichandran ◽  
Robin A. de Graaf ◽  
Henk M. De Feyter ◽  
...  

Increased glucose and choline uptake are hallmarks of cancer. We investigated whether the uptake and conversion of [2H9]choline alone and together with that of [6,6′-2H2]glucose can be assessed in tumors via deuterium metabolic imaging (DMI) after administering these compounds. Therefore, tumors with human renal carcinoma cells were grown subcutaneously in mice. Isoflurane anesthetized mice were IV infused in the MR magnet for ~20 s with ~0.2 mL solutions containing either [2H9]choline (0.05 g/kg) alone or together with [6,6′-2H2]glucose (1.3 g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 90° excitation pulse and 400 ms repetition time. 3D DMI was recorded at high resolution (2 × 2 × 2 mm) in 37 min or at low resolution (3.7 × 3.7 × 3.7 mm) in 2:24 min. Absolute tissue concentrations were calculated assuming natural deuterated water [HOD] = 13.7 mM. Within 5 min after [2H9]choline infusion, its signal appeared in tumor spectra representing a concentration increase to 0.3–1.2 mM, which then slowly decreased or remained constant over 100 min. In plasma, [2H9]choline disappeared within 15 min post-infusion, implying that its signal arises from tumor tissue and not from blood. After infusing a mixture of [2H9]choline and [6,6′-2H2]glucose, their signals were observed separately in tumor 2H spectra. Over time, the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6′-2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of 2H compounds, reconstructed from high resolution DMIs, showed their spatial tumor accumulation. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.


2021 ◽  
Vol 12 ◽  
Author(s):  
Beatriz Aragón-Aranda ◽  
Leyre Palacios-Chaves ◽  
Miriam Salvador-Bescós ◽  
María Jesús de Miguel ◽  
Pilar M. Muñoz ◽  
...  

The brucellae are facultative intracellular bacteria with a cell envelope rich in phosphatidylcholine (PC). PC is abundant in eukaryotes but rare in prokaryotes, and it has been proposed that Brucella uses PC to mimic eukaryotic-like features and avoid innate immune responses in the host. Two PC synthesis pathways are known in prokaryotes: the PmtA-catalyzed trimethylation of phosphatidylethanolamine and the direct linkage of choline to CDP-diacylglycerol catalyzed by the PC synthase Pcs. Previous studies have reported that B. abortus and B. melitensis possess non-functional PmtAs and that PC is synthesized exclusively via Pcs in these strains. A putative choline transporter ChoXWV has also been linked to PC synthesis in B. abortus. Here, we report that Pcs and Pmt pathways are active in B. suis biovar 2 and that a bioinformatics analysis of Brucella genomes suggests that PmtA is only inactivated in B. abortus and B. melitensis strains. We also show that ChoXWV is active in B. suis biovar 2 and conserved in all brucellae except B. canis and B. inopinata. Unexpectedly, the experimentally verified ChoXWV dysfunction in B. canis did not abrogate PC synthesis in a PmtA-deficient mutant, which suggests the presence of an unknown mechanism for obtaining choline for the Pcs pathway in Brucella. We also found that ChoXWV dysfunction did not cause attenuation in B. suis biovar 2. The results of these studies are discussed with respect to the proposed role of PC in Brucella virulence and how differential use of the Pmt and Pcs pathways may influence the interactions of these bacteria with their mammalian hosts.


Author(s):  
Santiago Schiaffino-Ortega ◽  
Elena Mariotto ◽  
Pilar María Luque-Navarro ◽  
María Kimatrai-Salvador ◽  
Ramon Hurtado-Guerrero ◽  
...  

Choline kinase inhibitors are an important class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here we present the characterization and the structure activity relationship of a series of non-symmetrical choline kinase inhibitors characterized by a 3-aminophenol moiety, bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium cationic heads through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and for their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the best inhibitory results were those connected to the linker by the N-atom (4a-h) and these results are supported by docking studies. The compounds with the best antiproliferative results were those connected to the linker by the O-atom (3a-h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is greater the shorter the length of the linker, while in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with a low toxicity in non-tumoral cells (e.g human peripheral lymphocytes) respect to cancer cells. These compounds were also able to induce to induce apoptosis in Jurkat leukemic cells without causing significative variations of cell cycle. It is worth to mention that these derivatives, beside their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.


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