Cancer Chemotherapy and Pharmacology

, Volume 61, Issue 2, pp 231–242 | Cite as

Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells

  • David H. Holman
  • Lorianne S. Turner
  • Ahmed El-Zawahry
  • Saeed Elojeimy
  • Xiang Liu
  • Jacek Bielawski
  • Zdzislaw M. Szulc
  • Kristi Norris
  • Youssef H. Zeidan
  • Yusuf A. Hannun
  • Alicja Bielawska
  • James S. Norris
Original Article

Abstract

Purpose

Alterations in ceramide metabolism have been reported in prostate cancer (PCa), resulting in escape of cancer cells from ceramide-induced apoptosis. Specifically, increased expression of lysosomal acid ceramidase (AC) has been shown in some primary PCa tissues and in several PCa cell lines. To determine if this represents a novel therapeutic target, we designed and synthesized LCL204, a lysosomotropic analog of B13, a previously reported inhibitor of AC

Methods

Prostate cancer cell lines were treated with LCL204 for varying times and concentrations. Effects of treatment on cytotoxicity, sphingolipid content, and apoptotic markers were assessed.

Results

Treatment of DU145 PCa cells resulted in increased ceramide and decreased sphingosine levels. Interestingly, LCL204 caused degradation of AC in a cathepsin-dependent manner. We also observed rapid destabilization of lysosomes and the release of lysosomal proteases into the cytosol following treatment with LCL204. Combined, these events resulted in mitochondria depolarization and executioner caspase activation, ultimately ending in apoptosis

Conclusions

These results provide evidence that treatment with molecules such as LCL204, which restore ceramide levels in PCa cells may serve as a new viable treatment option for PCa.

Keywords

Ceramide Lysosomes Apoptosis LCL204 B13 Acid ceramidase inhibitors 

Abbreviations

PCa

Prostate cancer

HRPC

Hormone-refractory prostate cancer

AC

Acid ceramidase

ASMase

Acid sphingomyelinase

LTR

LysoTracker Red

LMP

Lysosomal membrane permeabilization

Notes

Acknowledgements

We thank Rick Peppler of the MUSC Flow Cytometry Facility for acquisition of flow cytometry data. We would also like to thank the MUSC Lipidomics Core for the synthesis of sphingolipid reagents and sphingolipid analysis. This work was supported by NIH/NCI PO1 CA97132 and HCC/DOD N6311601MD10004.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • David H. Holman
    • 1
  • Lorianne S. Turner
    • 1
  • Ahmed El-Zawahry
    • 1
  • Saeed Elojeimy
    • 1
  • Xiang Liu
    • 1
  • Jacek Bielawski
    • 2
  • Zdzislaw M. Szulc
    • 2
  • Kristi Norris
    • 3
  • Youssef H. Zeidan
    • 2
  • Yusuf A. Hannun
    • 2
  • Alicja Bielawska
    • 2
  • James S. Norris
    • 1
  1. 1.Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Biochemistry and Molecular BiologyMedical University of South CarolinaCharlestonUSA
  3. 3.Biochemistry Section, Surgical Neurology BranchNational Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA

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