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Mol Cancer Ther. 2015 Dec;14(12):2744-52. doi: 10.1158/1535-7163.MCT-15-0279. Epub 2015 Oct 22.

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

Author information

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.

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.

PMID:
26494858
PMCID:
PMC4674301
DOI:
10.1158/1535-7163.MCT-15-0279
[Indexed for MEDLINE]
Free PMC Article

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