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Acid Ceramidase
The Experts below are selected from a list of 1413 Experts worldwide ranked by ideXlab platform
Daniele Piomelli – One of the best experts on this subject based on the ideXlab platform.
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Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells.
International journal of molecular sciences, 2021Co-Authors: Michele Lai, Daniele Piomelli, Veronica La Rocca, Rachele Amato, Giulia Freer, Mario Costa, Pietro Giorgio Spezia, Paola Quaranta, Giuseppe Lombardo, Mauro PistelloAbstract:Cutaneous melamelanoma is often resistant to therapy due to its high plasticity, as well as its ability to metabolise chemotherapeutic drugs. Sphingolipid signalling plays a pivotal role in its progression and metastasis. One of the ways melanoma alters sphingolipid rheostat is via over-expression of lysosomal Acid Ceramidase (AC), which catalyses the hydrolysis of pro-apoptotic long-chain ceramides into sphingosine and fatty Acid. In this report, we examine the role of Acid Ceramidase in maintaining cellular homeostasis through the regulation of autophagy and mitochondrial activity in melanoma cell lines. We show that under baseline conditions, wild-type melanoma cells had 3-fold higher levels of the autophagy marker, microtubule-associated proteins 1A/1B light chain 3B (LC3 II), compared to AC-null cells. This difference was further magnified after cell starvation. Moreover, we noticed autophagy impairment in A375 AC-null cells, possibly due to local accumulation of non-metabolized ceramides. Nonetheless, we observed that AC-null cells exhibited a significant increase in mitochondrial membrane potential compared to control cells. Consistent with this observation, we found that, after total starvation, ~30% of AC-null cells undergo apoptosis compared to ~6% of wild-type cells. As expected, AC transfection restored viability in A375 AC-null cells. Together, these findings suggest that AC-null melanoma cells change and adapt their metabolism to survive in the absence of AC, although in a way that does not allow them to cope with the stress of nutrient deprivation.
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Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells.
Scientific reports, 2017Co-Authors: Michele Lai, Natalia Realini, Mauro Pistello, Marco La Ferla, Ilaria Passalacqua, Giulia Matteoli, Anand K. Ganesan, Chiara Maria Mazzanti, Daniele PiomelliAbstract:Acid Ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty Acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy. Here we used CrispR–Cas9-mediated gene editing to delete the gene encoding for AC, ASAH1, in human A375 melanoma cells. ASAH1-null clones show significantly greater accumulation of long-chain saturated ceramides that are substrate for AC. As seen with administration of exogenous ceramide, AC ablation blocks cell cycle progprogression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for AC in maintaining malignancy and self-renewal of invasive melanoma cells. The results suggest that AC inhibitors might find therapeutic use as adjuvant therapy for advanced melanoma.
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pyrazole based Acid Ceramidase inhibitors design synthesis and structure activity relationships
Synthesis, 2016Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela PizziraniAbstract:Acid Ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.
Daniela Pizzirani – One of the best experts on this subject based on the ideXlab platform.
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pyrazole based Acid Ceramidase inhibitors design synthesis and structure activity relationships
Synthesis, 2016Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela PizziraniAbstract:Acid Ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.
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Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure–Activity Relationships
Synthesis, 2016Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela PizziraniAbstract:Acid Ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.
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Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure–Activity Relationship (SAR) Studies
Journal of medicinal chemistry, 2015Co-Authors: Anders Bach, Daniela Pizzirani, Natalia Realini, Valentina Vozella, Debora Russo, Ilaria Penna, Laurin Melzig, Rita Scarpelli, Daniele PiomelliAbstract:Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, Acid Ceramidase (AC), hydrolyzes these substances into sphingosine and fatty Acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.
Natalia Realini – One of the best experts on this subject based on the ideXlab platform.
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Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors.
Journal of medicinal chemistry, 2020Co-Authors: Simona Di Martino, Natalia Realini, Debora Russo, Ilaria Penna, Piero Tardia, Vincenzo Cilibrasi, Samantha Caputo, Marco Mazzonna, Natasha Margaroli, Marco MiglioreAbstract:Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid Ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher’s and Krabbe’s diseases. After daily intraperitoneal administration at 90 mg kg-1, 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathpathogenesis.
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Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells.
Scientific reports, 2017Co-Authors: Michele Lai, Natalia Realini, Mauro Pistello, Marco La Ferla, Ilaria Passalacqua, Giulia Matteoli, Anand K. Ganesan, Chiara Maria Mazzanti, Daniele PiomelliAbstract:Acid Ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty Acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy. Here we used CrispR-Cas9-mediated gene editing to delete the gene encoding for AC, ASAH1, in human A375 melanoma cells. ASAH1-null clones show significantly greater accumulation of long-chain saturated ceramides that are substrate for AC. As seen with administration of exogenous ceramide, AC ablation blocks cell cycle progression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for AC in maintaining malignancy and self-renewal of invasive melanoma cells. The results suggest that AC inhibitors might find therapeutic use as adjuvant therapy for advanced melanoma.
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pyrazole based Acid Ceramidase inhibitors design synthesis and structure activity relationships
Synthesis, 2016Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela PizziraniAbstract:Acid Ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.
Edward H. Schuchman – One of the best experts on this subject based on the ideXlab platform.
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Activity-Based Imaging of Acid Ceramidase in Living Cells.
Journal of the American Chemical Society, 2019Co-Authors: Yadira F Ordonez, Edward H. Schuchman, Thierry Levade, Virginie Garcia, Antonio Delgado, Jose Luis Abad, Mazen Aseeri, Josefina Casas, Mireia Casasampere, Gemma TriolaAbstract:Acid Ceramidase (AC) hydrolyzes ceramides into sphingoid bases and fatty Acids. The enzyme is overexpressed in several types of cancer and Alzheimer’s disease, and its genetic defect causes different incurable disorders. The availability of a method for the specific visualization of catalytically active AC in intracellular compartments is crucial for diagnosis and follow-up of therapeutic strategies in diseases linked to altered AC activity. This work was undertaken to develop activity-based probes for the detection of AC. Several analogues of the AC inhibitor SABRAC were synthesized and found to act as very potent (two-digit nM range) irreversible AC inhibitors by reaction with the active site Cys143. Detection of active AC in cell-free systems was achieved either by using fluorescent SABRAC analogues or by click chemistry with an azide-substituted analogue. The compound affording the best features allowed the unprecedented labeling of active AC in living cells.
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activity based imaging of Acid Ceramidase in living cells
Journal of the American Chemical Society, 2019Co-Authors: Yadira F Ordonez, Edward H. Schuchman, Thierry Levade, Virginie Garcia, Jose Luis Abad, Mazen Aseeri, Josefina Casas, Mireia Casasampere, Antonio DelgadoAbstract:Acid Ceramidase (AC) hydrolyzes ceramides into sphingoid bases and fatty Acids. The enzyme is overexpressed in several types of cancer and Alzheimer’s disease, and its genetic defect causes differe…
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Signalling Effects Induced by Acid Ceramidase in Human Epithelial Or Leukemic Cell Lines.
Cellular physiology and biochemistry : international journal of experimental cellular physiology biochemistry and pharmacology, 2019Co-Authors: Käthe Baduva, Edward H. Schuchman, Lara Büchter, Katja Kreyenkamp, Linnea Westphal, Barbara Wilker, Marcus Kohnen, Michael J. Edwards, Katrin Anne Becker, Erich GulbinsAbstract:BACKGROUND/AIMS Recent studies indicated that an inhalation treatment of cystic fibrfibrosis mice with Acid Ceramidase prevents and eliminates infections with Pseudomonas aeruginosa and Stapyhlococcus aureus. Inhalation of Acid Ceramidase facilitated the elimination of P. aeruginosa in acutely- or chronically-infected mice with cystic fibrfibrosis. Thus, inhalation of Acid Ceramidase might be a preventive and/or curative treatment for patients with cystic fibrfibrosis suffering from pneumonia. METHODS We treated cultured epithelial cells or leukemic T-lymphocytes (Jurkat cells) with purified Acid Ceramidase and determined intracellular signalling events, proliferation and cell survival. Specifically, we measured the activity of AKT, p38-kinase and p70S6-kinase using activation-specific phospho-antibodies in western blot studies. Trypan Blue staining served to analyze proliferation and cell survival. RESULTS Our studies indicate that treatment of Chang epithelial cells or Jurkat T lymphocytes with purified Acid Ceramidase results in a dose dependent activation of AKT, p38-kinase and p70S6-kinase, while tyrosine phosphorylation of intracellular proteins remains largely unchanged. Acid Ceramidase treatment did not change expression of tight junction proteins such as ZO-1, ZO-2 and occludin. Cellular viability and proliferation were not affected by Acid Ceramidase treatment. CONCLUSION Our data suggest that treatment of epithelial cells and lymphocytes with Acid Ceramidase results in activation of distinct pathways, in particular AKT- and p38K-dependent pathways, while no global activation or cell death was observed.
Xiang Liu – One of the best experts on this subject based on the ideXlab platform.
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Acid Ceramidase Promotes Nuclear Export of PTEN through Sphingosine 1-Phosphate Mediated Akt Signaling
PloS one, 2013Co-Authors: Thomas H. Beckham, James S Norris, Joseph C Cheng, S. Tucker Marrison, Xiang LiuAbstract:The tumor suppressor PTEN is now understood to regulate cellular processes at the cytoplasmic membrane, where it classically regulates PI3K signaling, as well as in the nucleus where multiple roles in controlling cell cycle and genome stability have been elucidated. Mechanisms that dictate nuclear import and, less extensively, nuclear export of PTEN have been described, however the relevance of these processes in disease states, particularly cancer, remain largely unknown. We investigated the impact of Acid Ceramidase on the nuclear-cytoplasmic trafficking of PTEN. Immunohistochemical analysis of a human prostate tisstissue micrmicroarray revealed that nuclear PTEN was lost in patients whose tumors had elevated Acid Ceramidase. We found that Acid Ceramidase promotes a reduction in nuclear PTEN that is dependent upon sphingosine 1-phosphate-mediated activation of Akt. We were further able to show that sphingosine 1-phosphate promotes formation of a complex between Crm1 and PTEN, and that leptomycin B prevents Acid Ceramidase and sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active exportin-mediated event. To investigate whether the tumor promoting aspects of Acid Ceramidase in prostate cancer depend upon its ability to export PTEN from the nucleus, we used enforced nuclear expression of PTEN to study docetaxel-induced apoptosis and cell killing, proliferation, and xenoengraftment. Interestingly, while Acid Ceramidase was able to protect cells expressing wild type PTEN from docetaxel, promote proliferation and xenoengraftment, Acid Ceramidase had no impact in cells expressing PTEN-NLS. These findings suggest that Acid Ceramidase, through sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting tumor formation, cell proliferation, and resistance to therapy.
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Autophagy is increased in prostate cancer cells overexpressing Acid Ceramidase and enhances resistance to C6 ceramide.
Prostate cancer and prostatic diseases, 2010Co-Authors: Lorianne S. Turner, James S Norris, Thomas H. Beckham, Joe Cheng, Thomas E. Keane, Xiang LiuAbstract:Autophagy is increased in prostate cancer cells overexpressing Acid Ceramidase and enhances resistance to C 6 ceramide
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Acid Ceramidase upregulation in prostate cancer: role in tumor development and implications for therapy.
Expert opinion on therapeutic targets, 2009Co-Authors: Xiang Liu, Saeed Elojeimy, Joseph C Cheng, Yusuf A Hannun, Thomas H. Beckham, Lorianne S. Turner, Alicja Bielawska, Thomas E. Keane, James S NorrisAbstract:Bioactive sphingolipids, such as ceramide, sphingosine and sphingosine-1-phosphate are known bio-effector molecules which play important roles in various aspects of cancer biology including cell proliferation, growth arrest, apoptosis, metastasis, senescence and inflammation. Therefore, enzymes involved in ceramide metabolism are gaining recognition as being critical regulators of cancer cell growth and/or survival. We previously observed that the ceramide metabolizing enzyme, Acid Ceramidase (AC) is upregulated in tumor tissues. Studies have now concluded that this creates a dysfunctional ceramide pathway, which is responsible for tumor progression and resistance to chemotherapy and radiation. This suggests that development of small-molecule drugs that inhibit AC enzyme activity is a promising approach for improving standard cancer therapy and patient’s clinical outcomes.