314 research outputs found

    Anticancer agents interacting with membrane glucose transporters

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    The altered metabolism observed in cancer cells generally consists of increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore, GLUTs are considered as suitable targets for treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents

    Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD.

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    Rhabdomyosarcoma is the most frequent soft tissue sarcoma in children and adolescents, with a high rate of relapse that dramatically affects the clinical outcome. Multiagent chemotherapy, in combination with surgery and/or radiation therapy, is the treatment of choice. However, the relapse rate is disappointingly high and identification of new therapeutic tools is urgently needed. Under this respect, the selective block of key features of cancer stem cells (CSC) appears particularly promising. In this study, we isolated rhabdomyosarcoma CSC with stem-like features (high expression of NANOG and OCT3/ 4, self-renewal ability, multipotency). Rhabdomyosarcoma CSC showed higher invasive ability and a reduced cytotoxicity to doxorubicin in comparison to native cells, through a mechanism unrelated to the classical multidrug resistance process. This was dependent on a high level of lysosome acidity mediated by a high expression of vacuolar ATPase (V-ATPase). Since it was not associated with other paediatric cancers, like Ewing\u2019s sarcoma and neuroblastoma, V-ATPase higher expression in CSC was rhabdomyosarcoma specific. Inhibition of lysosomal acidification by the V-ATPase inhibitor omeprazole, or by specific siRNA silencing, significantly enhanced doxorubicin cytoxicity. Unexpectedly, lysosomal targeting also blocked cell growth and reduced the invasive potential of rhabdomyosarcoma CSC, even at very low doses of omeprazole (10 and 50 mM, respectively). Based on these observations, we propose lysosome acidity as a valuable target to enhance chemosensitivity of rhabdomyosarcoma CSC, and suggest the use of anti-V-ATPase agents in combination with standard regimens as a promising tool for the eradication of minimal residual disease or the prevention of metastatic disease

    Spectral Analysis of Ultrasonic and Photo Acoustic Signals Generated by a Prototypal Fiber Microprobe for Media Characterization

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    AbstractCombination of photoacoustics and ultrasound can provide complemental features and mutual benefits, useful for a complete tissue characterization and consequently for early diagnosis or therapy monitoring. Furthermore, minimally invasive techniques are required both to reach organs or tissue not accessible and to reduce patient discomfort and costs. This work has tested a prototypal microprobe for media characterization analysing their optical and mechanical features. Two different transmitters compose the miniaturized probe: one for large bandwidth ultrasonic signals generation and one for guiding the laser light into tissue to photogenerate ultrasound. The aim is to evaluate the possibility of employing in the future this new type of microprobe to characterize internal tissue, combining ultrasound and photoacoustic investigations. A calibrated commercial hydrophone has been used to detect generated signals, with the aim to provide repeatable and reliable results. Dedicated test objects have been realized by using solutions of corn starch flour and of Chinese ink with different and calibrated dilutions. The spectral algorithm HyperSPACE (Hyper SPectral Analysis for Characterization in Echography), applied on ultrasonic and photoacoustic signals has allowed differentiating scatterers' concentration and distribution

    Salicylketoximes as inhibitors of Glucose Transporters

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    Some derivatives of the 4-arylsalicylketoximes series displayed inhibitory effects on glucose transport and on cell proliferation in several biological assays,[1] resulting to be effective GLUT1 inhibitors also in GLUT1-containing giant vesicles. GLUT1 is one of the 14 glucose transporter isoforms, widely overexpressed in many cancer types. Thus, for the discovered properties, the oximes of interest represent interesting candidates for anticancer therapy. Variously substituted 4-arylsalicylketoximes (3, Fig.1) were synthetized via Suzuki cross-coupling and a subsequent condensation of the resulting biaryl-ketone intermediates with hydroxylamine hydrochloride. [1] Rat GLUT1 membrane proteins were produced by Pichia Pastoris cultures, and purified following GLUT1 purification protocols, [2] which were largely revised to avoid the protein cleavage. Compounds 3a, 3b, 3e, and 3f efficiently inhibited glucose uptake in GLUT1-containing giant vesicle assays. [3] To study the nature of the binding process between GLUT1 and the synthetic compounds, many crystallization attempts were set up with 3a and 3e using Lipidic Cubic Phase method, which produced many small crystals. Since many isoforms of GLUTs are overexpressed in cancer cells, inhibition of other GLUT isoforms, such as GLUT3, will be tested in the near future. In conclusion, 4-arylsalicylketoximes showed good inhibition of GLUT1 isoform. First results from GLUT3-giant vesicles assays revealed that, within this series of compounds, 3a is the most selective GLUT1-inhibitor. Further assays with GLUTs-containing giant vesicle and crystallization attempts are currently underway. [1] Granchi C, Qian Y, Lee H.Y, Paterni I, Pasero C, Iegre J, Carlson K. E, Tuccinardi T, Chen X, Katzenellenbogen J. A, Hergenrother P. J, Minutolo F, ChemMedChem. 2015; 1892–1900. [2] Venskutonyté R, Elbing K, Lindkvist-Petersson K, Methods Mol Biol. 2018; 1713, 1–13. [3] Hansen J.H, Elbing K, Thompson J.R, Malmstadt N, Lindkvist-Petersson K, Chem. Commun. 2015; 51, 2316–2319

    Stard3: A prospective target for cancer therapy

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    Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo-and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity

    GLUT1 and LOX inhibitors as perspective anticancer agents tackling glucose avidity and ECM remodeling in tumors

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    Introduction Most cancers have large hypoxic regions, which display an increase of the glycolytic metabolism leading to the production of lactate, providing cancer cells with adequate amounts of energy and anabolites. To this end, tumor cells generally overexpress glucose transporters (GLUTs), in particular GLUT1, which results in an increased uptake of glucose to support their less efficient energy production (Warburg effect). Therefore, therapeutic interventions aimed at reducing cancer glycolysis may be implemented by several strategies, including the development of inhibitors of glucose transporters. Furthermore, extracellular matrix (ECM) remodeling is one of the key processes preluding metastatic invasion, and it is promoted by several effectors, such as lysyl oxidase (LOX), an enzyme commonly involved in extracellular matrix maturation. LOX is up-regulated by HIF-1 and plays a critical role in the development of metastasis. Therefore, LOX inhibitors may represent an additional and innovative strategy for the treatment and the prevention of metastatic cancer. Methods We have developed various classes of compounds that are able to interfere with GLUTs (Granchi et al. 2015, Tuccinardi et al. 2013) and LOX (Granchi et al. 2009) by molecular design and chemical synthesis. Their effect on cell proliferation, apoptosis, migration and other key determinants of activity were evaluated by sulforhodamine-B and luciferase assays, FACS, wound-healing assay, and Quantitative PCR. The studies were performed in seven PDAC cells, including five primary-cell-cultures and 3D co-cultures with human stellate cells, in normoxic and hypoxic conditions. Results The IC50s of the tested compounds ranged from 13.9 to 32.0 μM after 72-hour exposure. Notably, these compounds were still active in 3D co-cultures of these tumor cells with pancreatic stellate cells, which showed increased resistance to gemcitabine and are more representative of the dense stromal compartment with core hypoxic areas of this tumor type, as detected by immunohistochemical stainings. Remarkably, one compound (PGL-14) showed a synergistic interaction with gemcitabine, increasing apoptosis induction and accumulation of ROS. Furthermore, the combination of these drugs reduced cell migration and enhanced in vitro sensitivity to anoikis, suggesting the ability of these compounds to inhibit metastasis. Discussion GLUT1 inhibitors were more active in hypoxia, but still active also in normoxia. Conversely, we did not detect cytotoxic effects using the LOX-inhibitors in normoxia (at concentration until 50 μM) since they were designed as bioreductively activated prodrugs, which are therefore activated only under hypoxic conditions. However, at O2 tension of 1%, IC50s were below 10 μM. As reported previously, LOX inhibition was associated with reduction of the mRNA levels of fibronectin, suggesting that it might also have impact on the interaction of tumor cells with the stroma that are mediated by integrins and fibronectin, regulating tissue stiffness (Coppola et al. 2017). Conclusion Interventions aimed at blocking the glycolytic activity or the extracellular matrix remodeling of tumors by means of newly designed molecules proved to exert a synergistic effect with clinically approved drugs, such as gemcitabine. These results seem to support the strategy of the simultaneous GLUT/LOX-inhibition in order to further sensitize hypoxic cancer portions to chemotherapy. Bibliography C. Granchi, et al. ChemMedChem 2009, 4, 1590-1594. C. Granchi, et al. ChemMedChem 2015, 10, 1892-1900. T. Tuccinardi, et al. Bioorg. Med. Chem. Lett. 2013, 23, 6923-6927. Coppola S, et al. Drug Resist Updat. 2017, 31, 43-51

    Glucose transporters: production, crystallization and inhibition

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    Glucose transporters (GLUTs) comprise a family of 14 membrane proteins that regulate glucose uptake into the cell. Different types of GLUTs are expressed in various tissues and play a crucial role in glucose metabolism. Cancer cells are highly dependant on glucose and therefore GLUTs are possible drug targets for cancer therapy. In order to block the glucose uptake facilitated by GLUTs, various inhibitors are studied and both natural and synthetic compounds having an inhibitory effect on glucose uptake have been discovered. High resolution X-ray structure of the GLUT-inhibitor complex would provide a detailed understanding of protein-inhibitor interactions and contribute to facilitating the development of new derivatives. The focus of this study is on a glucose transporter 1 (GLUT1). The GLUT1 has been produced and crystallization trials set up, which resulted in microcrystals. A series of salicylketoxime based compounds have been shown to inhibit GLUT1 and two lead compounds displaying the highest inhibition have been identified in a giant vesicle assay. The main goal of the study is to determine the structure of the GLUT1 with selected inhibitors. Moreover, studies on one more glucose transporter GLUT3 are carried out to investigate the selectivity of the salcylketoxime compounds
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