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Targeting the Sphingolipid Metabolic Pathway: Promotion from Benchwarmer to the...
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Targeting the Sphingolipid Metabolic Pathway: Promotion from Benchwarmer to the Starting Lineup—a Themed Issue in Memory of Dr’s. Lina Obeid and Mark Kester

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 5491

Special Issue Editor

Dr. Jeremy A. Hengst

E-Mail Website
Guest Editor
Department of Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Interests: sphingolipid metabolism; sphingolipid therapeutic development/mechanism of action; acute myeloid leukemia

Special Issue Information

Dear Colleagues,

We have lost two dear friends, colleagues, and mentors in the past few years. The passing of Drs. Lina Obeid and Mark Kester remind us all to cherish each moment with our families, friends, and colleagues. In their honor, I invite you to submit a manuscript to this Special Issue of Cancers entitled “Targeting the Sphingolipid Metabolic Pathway: Promotion from Benchwarmer to the Starting Lineup”.

The title is an homage to a review that Christopher Gault and Lina Obeid published 12 years ago: “Still Benched on Its Way to the Bedside: Sphingosine Kinase 1 as an Emerging Target in Cancer Chemotherapy”. In this review, they noted the considerable challenges in trying to develop clinically relevant therapeutic strategies targeting sphingosine kinase 1. Looking at the broader sphingolipid field 12 years later, we have seen some successes—for example, fingolimod and ozanimod for relapsing remitting multiple sclerosis, opaganib for cancer and COVID-19, and nanoliposomal ceramides for cancer. There are also a number of areas of study with great therapeutic potential in the future. I feel that now is a good time for all of us to reflect on and to highlight the strides we have made in development of therapeutic strategies targeting the sphingolipid metabolic pathways in the fight against cancer.

This Special Issue is designed to assemble important studies in the area of targeted therapies directed toward sphingolipid metabolizing enzymes as anticancer strategies, either as standalone therapies, novel combinatorial therapies, or as adjuvants to existing therapies.  I am sure that I am not alone in my feeling that it was an honor to know both Lina and Mark. I am pleased to invite you to submit an article to this Special Issue as an acknowledgment of their dedication and leadership.  

Dr. Jeremy A. Hengst
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sphingolipid metabolic pathways
  • targeted therapeutics
  • cancer
  • drug resistance
  • rational drug combinations

Published Papers (4 papers)

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Research

Jump to: Review

22 pages, 6661 KiB  
Article
Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia
by Johnson Ung, Su-Fern Tan, Todd E. Fox, Jeremy J. P. Shaw, Maansi Taori, Bethany J. Horton, Upendarrao Golla, Arati Sharma, Zdzislaw M. Szulc, Hong-Gang Wang, Charles E. Chalfant, Myles C. Cabot, David F. Claxton, Thomas P. Loughran, Jr. and David J. Feith
Cancers 2023, 15(24), 5866; https://doi.org/10.3390/cancers15245866 - 15 Dec 2023
Viewed by 1094
Abstract
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and [...] Read more.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide. Full article
(This article belongs to the Special Issue Targeting the Sphingolipid Metabolic Pathway: Promotion from Benchwarmer to the Starting Lineup—a Themed Issue in Memory of Dr’s. Lina Obeid and Mark Kester)
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22 pages, 4304 KiB  
Article
Simultaneous Inhibition of Ceramide Hydrolysis and Glycosylation Synergizes to Corrupt Mitochondrial Respiration and Signal Caspase Driven Cell Death in Drug-Resistant Acute Myeloid Leukemia
by Kelsey H. Fisher-Wellman, Miki Kassai, James T. Hagen, P. Darrell Neufer, Mark Kester, Thomas P. Loughran, Jr., Charles E. Chalfant, David J. Feith, Su-Fern Tan, Todd E. Fox, Johnson Ung, Gemma Fabrias, Jose’ Luis Abad, Arati Sharma, Upendarrao Golla, David F. Claxton, Jeremy J. P. Shaw, Debajit Bhowmick and Myles C. Cabot
Cancers 2023, 15(6), 1883; https://doi.org/10.3390/cancers15061883 - 21 Mar 2023
Cited by 2 | Viewed by 2039
Abstract
Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and [...] Read more.
Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and glycosylation has been shown to be an element in chemotherapy-resistant AML, a problem considering the crucial role ceramide plays in eliciting apoptosis. Herein we employed agents that block ceramide clearance to determine if such a “reset” would be of therapeutic benefit. SACLAC was utilized to limit ceramide hydrolysis, and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) was used to block the glycosylation route. The SACLAC D-threo-PDMP inhibitor combination was synergistically cytotoxic in drug-resistant, P-glycoprotein-expressing (P-gp) AML but not in wt, P-gp-poor cells. Interestingly, P-gp antagonists that can limit ceramide glycosylation via depression of glucosylceramide transit also synergized with SACLAC, suggesting a paradoxical role for P-gp in the implementation of cell death. Mechanistically, cell death was accompanied by a complete drop in ceramide glycosylation, concomitant, striking increases in all molecular species of ceramide, diminished sphingosine 1-phosphate levels, resounding declines in mitochondrial respiratory kinetics, altered Akt, pGSK-3β, and Mcl-1 expression, and caspase activation. Although ceramide was generated in wt cells upon inhibitor exposure, mitochondrial respiration was not corrupted, suggestive of mitochondrial vulnerability in the drug-resistant phenotype, a potential therapeutic avenue. The inhibitor regimen showed efficacy in an in vivo model and in primary AML cells from patients. These results support the implementation of SL enzyme targeting to limit ceramide clearance as a therapeutic strategy in chemotherapy-resistant AML, inclusive of a novel indication for the use of P-gp antagonists. Full article
(This article belongs to the Special Issue Targeting the Sphingolipid Metabolic Pathway: Promotion from Benchwarmer to the Starting Lineup—a Themed Issue in Memory of Dr’s. Lina Obeid and Mark Kester)
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Review

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15 pages, 3942 KiB  
Review
Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy
by Hiroyuki Nojima, Hiroaki Shimizu, Takashi Murakami, Kiyohiko Shuto and Keiji Koda
Cancers 2024, 16(5), 850; https://doi.org/10.3390/cancers16050850 - 20 Feb 2024
Viewed by 755
Abstract
The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine [...] Read more.
The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases. Full article
(This article belongs to the Special Issue Targeting the Sphingolipid Metabolic Pathway: Promotion from Benchwarmer to the Starting Lineup—a Themed Issue in Memory of Dr’s. Lina Obeid and Mark Kester)
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19 pages, 1795 KiB  
Review
Therapeutic Potential for Sphingolipids in Inflammatory Bowel Disease and Colorectal Cancer
by Keila S. Espinoza and Ashley J. Snider
Cancers 2024, 16(4), 789; https://doi.org/10.3390/cancers16040789 - 15 Feb 2024
Cited by 1 | Viewed by 862
Abstract
Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids that regulate cell signaling, differentiation, apoptosis, [...] Read more.
Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids that regulate cell signaling, differentiation, apoptosis, inflammation, and survival. The balance between ceramide (Cer), the central sphingolipid involved in apoptosis and differentiation, and sphingosine-1-phosphate (S1P), a potent signaling molecule involved in proliferation and inflammation, is vital for the maintenance of normal cellular function. Altered sphingolipid metabolism has been implicated in IBD and CRC, with many studies highlighting the importance of S1P in inflammatory signaling and pro-survival pathways. A myriad of sphingolipid analogues, inhibitors, and modulators have been developed to target the sphingolipid metabolic pathway. In this review, the efficacy and therapeutic potential for modulation of sphingolipid metabolism in IBD and CRC will be discussed. Full article
(This article belongs to the Special Issue Targeting the Sphingolipid Metabolic Pathway: Promotion from Benchwarmer to the Starting Lineup—a Themed Issue in Memory of Dr’s. Lina Obeid and Mark Kester)
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