2. Academic Validation
  3. Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia

Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia

  • Mol Cancer Res. 2020 Mar;18(3):352-363. doi: 10.1158/1541-7786.MCR-19-0619.
Jennifer M Pearson 1,  Su-Fern Tan 2,  Arati Sharma 3 4,  Charyguly Annageldiyev 3,  Todd E Fox 5,  Jose Luis Abad 6,  Gemma Fabrias 6,  Dhimant Desai 4,  Shantu Amin 4,  Hong-Gang Wang 3 7,  Myles C Cabot 8,  David F Claxton 3,  Mark Kester 4 9,  David J Feith 2 9,  Thomas P Loughran 10 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
  • 2 Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia.
  • 3 Penn State Cancer Institute, Hershey, Pennsylvania.
  • 4 Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
  • 5 Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
  • 6 Department of Biological Chemistry, Networking Biomedical Research Centre on Liver and Digestive Diseases (CIBER-EHD), Institute for Advanced Chemistry of Catalonia, Spanish National Research Council (IQAC-CSIC), Barcelona, Spain.
  • 7 Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
  • 8 Department of Biochemistry and Molecular Biology, East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
  • 9 University of Virginia Cancer Center, Charlottesville, Virginia.
  • 10 Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia. TL7CS@virginia.edu.
PMID: 31744877 DOI: 10.1158/1541-7786.MCR-19-0619
Abstract

Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. The 5-year survival rate is approximately 25%, and recent therapeutic developments have yielded little survival benefit. Therefore, there is an urgent need to identify novel therapeutic targets. We previously demonstrated that acid Ceramidase (ASAH1, referred to as AC) is upregulated in AML and high AC activity correlates with poor patient survival. Here, we characterized a novel AC inhibitor, SACLAC, that significantly reduced the viability of AML cells with an EC50 of approximately 3 μmol/L across 30 human AML cell lines. Treatment of AML cell lines with SACLAC effectively blocked AC activity and induced a decrease in sphingosine 1-phosphate and a 2.5-fold increase in total ceramide levels. Mechanistically, we showed that SACLAC treatment led to reduced levels of splicing factor SF3B1 and alternative Mcl-1 mRNA splicing in multiple human AML cell lines. This increased proapoptotic MCL-1S levels and contributed to SACLAC-induced Apoptosis in AML cells. The apoptotic effects of SACLAC were attenuated by SF3B1 or Mcl-1 overexpression and by selective knockdown of MCL-1S. Furthermore, AC knockdown and exogenous C16-ceramide supplementation induced similar changes in SF3B1 level and MCL-1S/L ratio. Finally, we demonstrated that SACLAC treatment leads to a 37% to 75% reduction in leukemic burden in two human AML xenograft mouse models. IMPLICATIONS: These data further emphasize AC as a therapeutic target in AML and define SACLAC as a potent inhibitor to be further optimized for future clinical development.

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