SK1-I attenuated growth, migration, and invasion of many GBM cell lines, and drastically lowered tumor growth and vascularization in mice bearing each subcutaneous and orthotopic glioblastoma xenografts. The profound effects of SK1-I were attributed to suppression of Akt activation and subsequent interruption of signaling through the Akt pathway,which is upregulated in the majority of glioblastomas (Kapitonov et al., 2009). It must also be noted that SK1-I was found to additional enhance cell deathwhen applied in combinationwith inhibitors B-Raf mutation of other cancer-related signaling pathways. This type of mixture therapy is emerging as an important technique in the management of malignancies in general and is very important for those in which very efficacious therapeutic remedies are lacking, including head and neck cancer. In that vein, a recently completed Phase I clinical trial examined the use on the SphK1 inhibitor safingol in combination with cisplatin to treat patients with advanced solid tumors. Although this perform is still in its early stages, the published findings indicate that the drug combination was very properly tolerated and some degree of disease regression was observed (Dickson et al.
, 2011). Modulation of SphK1/S1P signaling can also guide overcome resistance to chemo- and radio-therapy in cancer cells. Resistance to therapeutic intervention is really a really serious difficulty in cancer management, contributing drastically to morbidity and mortality associated with the illness. In this regard, siRNA knockdown or chemical inhibition of SphK1 can sensitize cancer cell lines which are resistant to conventional remedies (Pyne & Pyne, 2010). Meanwhile, the mechanisms underlying these significant observations are nevertheless being unraveled. The S1P/ceramide rheostat has been identified CCI-779 as one from the critical determinants of pancreatic cancer cell sensitivity (Guillermet-Guibert et al., 2009). Pancreatic cancer cells resistant to gemcitabine, a chemotherapeutic nucleoside analog, had high expression of SphK1 and an abnormally low ceramide/S1P ratio. Remarkably, these resistant cells developed gemcitabine sensitivity following upregulation with the ceramide/S1P ratio together with the SphK inhibitor 2-(p-hydroxyanilino)- 4-(p-chlorophenyl) thiazole (Guillermet-Guibert et al., 2009), referred to as SKI. Along these lines, it has been proposed that SphK inhibition by the immunosuppressive sphingosine analog FTY-720 is responsible for increased radiotherapeutic sensitivity of prostate cancer cells in culture as properly as in subcutaneous and orthotopic murine xenografts (Pchejetski et al., 2010).