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

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.

• Authors: Dimitri Pchejetski, Nicolas Doumerc, Muriel Golzio, Maria Naymark, Justin Teissié, Takafumi Kohama, Jonathan Waxman, Bernard Malavaud, Olivier Cuvillier
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 7 Pg. 1836-45 (Jul 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18644996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• B 5354c
• Ceramides
• Lysophospholipids
• para-Aminobenzoates
• Green Fluorescent Proteins
• sphingosine 1-phosphate
• Irinotecan
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Caspases
• Sphingosine
• 4-Aminobenzoic Acid
• Camptothecin

Topics

• 4-Aminobenzoic Acid (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Camptothecin (analogs & derivatives, pharmacology, therapeutic use)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Ceramides (metabolism)
• Drug Therapy, Combination
• Green Fluorescent Proteins (metabolism)
• Humans
• Irinotecan
• Lysophospholipids (metabolism)
• Male
• Mice
• Neoplasm Metastasis
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors)
• Prostatic Neoplasms (drug therapy, enzymology)
• Sphingosine (analogs & derivatives, metabolism)
• Treatment Outcome
• Xenograft Model Antitumor Assays
• para-Aminobenzoates