Sphingosine kinase‐1 inhibition sensitizes curcumin‐induced growth inhibition and apoptosis in ovarian cancer cells

Recent published studies suggest that increasing levels of ceramides enhance the chemo‐sensitivity of curcumin. Using in vitro approaches, we analyzed the impact of sphingosine kinase‐1 ( S ph K ‐1) inhibition on ceramide production, and evaluated SphK1 inhibitor II ( SKI ‐ II ) as a potential curcumin chemo‐sensitizer in ovarian cancer cells. We found that S ph K 1 is overexpressed in ovarian cancer patients' tumor tissues and in cultured ovarian cancer cell lines. Inhibition of S ph K 1 by SKI ‐ II or by RNA interference ( RNA i) knockdown dramatically enhanced curcumin‐induced apoptosis and growth inhibition in ovarian cancer cells. SKI ‐ II facilitated curcumin‐induced ceramide production, p38 activation and A kt inhibition. Inhibition of p38 by the pharmacological inhibitor ( SB 203580), a dominant‐negative expression vector, or by RNA i diminished curcumin and SKI ‐ II co‐administration‐induced ovarian cancer cell apoptosis. In addition, restoring A kt activation introducing a constitutively active A kt, or inhibiting ceramide production by fumonisin B 1 also inhibited the curcumin plus SKI ‐ II co‐administration‐induced in vitro anti‐ovarian cancer effect, suggesting that ceramide accumulation, p38 activation and A kt inhibition are downstream effectors. Our findings suggest that low, well‐tolerated doses of SKI ‐ II may offer significant improvement to the clinical curcumin treatment of ovarian cancer. ( Cancer Sci , doi: 10.1111/j.1349‐7006.2012.02335.x, 2012)