Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models

Dmitry Pchejetski, Nicolas Doumerc, Muriel Golzio, Maria Naymark, Justin Teissié, Takafumi Kohama, Jonathan Waxman, Bernard Malavaud, Olivier Cuvillier

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)

Abstract

We have previously reported that, in prostate cancer, inhibition of the oncogenic sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway is a key element in chemotherapy-induced apoptosis. Here, we show that selective pharmacologic inhibition of SphK1 triggers apoptosis in LNCaP and PC-3 prostate cancer cells, an effect that is reversed by SphK1 enforced expression. More importantly, we show for the first time that the up-regulation of the SphK1/S1P pathway plays a crucial role in the resistance of prostate cancer cells to chemotherapy. Importantly, pharmacologic SphK1 inhibition with the B-5354c compound sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to S1P sphingolipid ratio. To conclude, our study highlights the notion that drugs specifically designed to inhibit SphK1 could provide a means of enhancing the effects of conventional treatment through the prosurvival antiapoptotic SphK1/S1P pathway.
Original languageEnglish
Pages (from-to)1836-45
Number of pages10
JournalMolecular Cancer Therapeutics
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 2008

Keywords

  • 4-Aminobenzoic Acid
  • Animals
  • Antineoplastic Agents
  • Apoptosis
  • Camptothecin
  • Caspases
  • Cell Line, Tumor
  • Cell Survival
  • Ceramides
  • Drug Therapy, Combination
  • Green Fluorescent Proteins
  • Humans
  • Lysophospholipids
  • Male
  • Mice
  • Neoplasm Metastasis
  • Phosphotransferases (Alcohol Group Acceptor)
  • Prostatic Neoplasms
  • Sphingosine
  • Treatment Outcome
  • Xenograft Model Antitumor Assays
  • para-Aminobenzoates

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