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      The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo.

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          Abstract

          Despite recent advances in the development of novel therapies against castration-resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product, sphingosine-1-phosphate, can promote proliferation, drug resistance, angiogenesis, and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration-resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor, while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640-treated mice contained significantly higher levels of C16- and C24:1-ceramides (but not dihydro-C16-ceramide) compared with vehicle-treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase, thereby providing a foundation for future exploration of this small-molecule inhibitor for the treatment of advanced disease.

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          Author and article information

          Journal
          Mol. Cancer Ther.
          Molecular cancer therapeutics
          American Association for Cancer Research (AACR)
          1538-8514
          1535-7163
          Dec 2015
          : 14
          : 12
          Affiliations
          [1 ] Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
          [2 ] Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
          [3 ] Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina.
          [4 ] Department of Hematology and Oncology, Medical University of South Carolina, Charleston, South Carolina.
          [5 ] Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
          [6 ] Apogee Biotechnology Corporation, Hummelstown, Pennsylvania.
          [7 ] Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina. johnsocv@musc.edu.
          Article
          1535-7163.MCT-15-0279 NIHMS733224
          10.1158/1535-7163.MCT-15-0279
          4674301
          26494858

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