Fisher-Wellman 2023 Cancers (Basel)
| Fisher-Wellman KH, Kassai M, Hagen JT, Neufer PD, Kester M, Loughran TP Jr, Chalfant CE, Feith DJ, Tan SF, Fox TE, Ung J, Fabrias G, Abad JL, Sharma A, Golla U, Claxton DF, Shaw JJP, Bhowmick D, Cabot MC (2023) Simultaneous inhibition of ceramide hydrolysis and glycosylation synergizes to corrupt mitochondrial respiration and signal caspase driven cell death in drug-resistant acute myeloid leukemia. https://doi.org/10.3390/cancers15061883 |
Β» Cancers (Basel) 15:1883. PMID: 36980769 Open Access
Fisher-Wellman Kesley H, Kassai Miki, Hagen James T, Neufer P Darrell, Kester Mark, Loughran Jr Thomas P, Chalfant Charles E, Feith David J, Tan Su-Fern, Fox Todd E, Ung Johnson, Fabrias Gemma, Abad Jose Luis, Sharma Arati, Golla Upendarrao, Claxton David F, Shaw Jeremy JP, Bhowmick Debajit, Cabot Myles C (2023) Cancers (Basel)
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 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-3Ξ², 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. β’ Keywords: P-glycoprotein, Acute myeloid leukemia, Ceramide, Chemotherapy resistance, Sphingolipids β’ Bioblast editor: Plangger M β’ O2k-Network Lab: US NC Greenville Neufer PD
Labels: MiParea: Respiration, Patients, Pharmacology;toxicology
Pathology: Cancer
Organism: Human Tissue;cell: Blood cells Preparation: Permeabilized cells, Intact cells
Coupling state: LEAK, ROUTINE, ET
Pathway: F, N, NS, ROX
HRR: Oxygraph-2k
2023-07, PBMCs
