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.
Highlights
Prostate cancer is the leading cancer in the male population and its management remains a complex problem [1]
We recently reported that the efficacy of docetaxel and camptothecin in prostate cancer cell and mouse models correlated with the shift of the ceramide to sphingosine 1phosphate (S1P) ratio toward proapoptotic ceramide [6]
We have previously reported that limited efficacy of camptothecin in PC-3 and docetaxel in LNCaP cells was associated with a transient paradoxical increase in sphingosine kinase-1 (SphK1) activity, suggesting that SphK1 stimulation might compromise chemotherapy success [6]
Summary
Prostate cancer is the leading cancer in the male population and its management remains a complex problem [1]. For men with advanced disease, chemotherapy may be offered after failure of hormonal therapy. Systemic chemotherapy has been evaluated in men with hormone-refractory prostate cancer for many years, with two effective compounds identified. The microtubules, targeted by camptothecins and docetaxel, seem to be a relevant target in hormone-refractory prostate cancer as shown by the survival improvement observed in docetaxel-based randomized phase III trials [2, 3]. The U.S Food and Drug Administration recently approved docetaxel as standard first-line therapy in patients with metastatic hormone-refractory prostate cancer. It has been recently suggested that camptothecin analogues might be of clinical relevance both in hormonerefractory prostate cancer patients as a first-line chemotherapy [4] and in patients who failed one prior cytotoxic chemotherapy [5]
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