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Acid Ceramidase

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Daniele Piomelli – One of the best experts on this subject based on the ideXlab platform.

  • Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells.
    International journal of molecular sciences, 2021
    Co-Authors: Michele Lai, Daniele Piomelli, Veronica La Rocca, Rachele Amato, Giulia Freer, Mario Costa, Pietro Giorgio Spezia, Paola Quaranta, Giuseppe Lombardo, Mauro Pistello
    Abstract:

    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.

  • Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells.
    Scientific reports, 2017
    Co-Authors: Michele Lai, Natalia Realini, Mauro Pistello, Marco La Ferla, Ilaria Passalacqua, Giulia Matteoli, Anand K. Ganesan, Chiara Maria Mazzanti, Daniele Piomelli
    Abstract:

    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 CrispRCas9-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.

  • pyrazole based Acid Ceramidase inhibitors design synthesis and structure activity relationships
    Synthesis, 2016
    Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela Pizzirani
    Abstract:

    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.

  • pyrazole based Acid Ceramidase inhibitors design synthesis and structure activity relationships
    Synthesis, 2016
    Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela Pizzirani
    Abstract:

    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.

  • Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure–Activity Relationships
    Synthesis, 2016
    Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela Pizzirani
    Abstract:

    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.

  • Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure–Activity Relationship (SAR) Studies
    Journal of medicinal chemistry, 2015
    Co-Authors: Anders Bach, Daniela Pizzirani, Natalia Realini, Valentina Vozella, Debora Russo, Ilaria Penna, Laurin Melzig, Rita Scarpelli, Daniele Piomelli
    Abstract:

    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.

  • Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors.
    Journal of medicinal chemistry, 2020
    Co-Authors: Simona Di Martino, Natalia Realini, Debora Russo, Ilaria Penna, Piero Tardia, Vincenzo Cilibrasi, Samantha Caputo, Marco Mazzonna, Natasha Margaroli, Marco Migliore
    Abstract:

    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.

  • Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells.
    Scientific reports, 2017
    Co-Authors: Michele Lai, Natalia Realini, Mauro Pistello, Marco La Ferla, Ilaria Passalacqua, Giulia Matteoli, Anand K. Ganesan, Chiara Maria Mazzanti, Daniele Piomelli
    Abstract:

    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.

  • pyrazole based Acid Ceramidase inhibitors design synthesis and structure activity relationships
    Synthesis, 2016
    Co-Authors: Eleonora Diamanti, Daniele Piomelli, Natalia Realini, Chiara Pagliuca, Giovanni Bottegoni, Luca Goldoni, Fabio Bertozzi, Daniela Pizzirani
    Abstract:

    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.

Xiang Liu – One of the best experts on this subject based on the ideXlab platform.