And Res synergically inhibit SphK1 activity, through a novel ERK/PLD-dependent mechanism in prostate cancer cells (C4-2B hormone-responsive and PC-3 hormone- refractory) acting as a possible anti-cancer effector [40]. According to Scarlatti et al. [119] activation in the de novo Cer synthesis by Res will be the mechanism underlying its growth inhibitory effect around the metastatic, drug-resistant and highly invasive breast cancer cell line MDA-MB-231. This accumulation derives from each de novo Cer synthesis and SM hydrolysis by activation respectively of SPT and nSMase. A different function by Scarlatti et al. [120] presented that pretreatment with Res enhances tumor cell killing and inhibits the clonogenic survival in resistant irradiated-DU145 prostate cancer cells, synergistically affecting the cellular response to ionizing radiation. This event was mediated by a rise in cellular de novo Cer levels. Dolfini et al. [121] demonstrated that targeting Cer signaling with Res may well provide a possible approach to prevent the growth of hormone-independent breast cancer. Res exerts a severe inhibitory effect around the development of MDA-MB-231 both in vitro and in vivo. It impacts the aggregation properties of MDA-MB-231 cells into multicellular tumor spheroids in association with induction of de novo synthesis of Cer. Minutolo et al. [122] showed that a synthesized derivative of Res [5-(6-hydroxynaphthalen-2-yl)benzene-1,3-diol] is extra powerful in triggering apoptosis, coupled together with the induction of endogenous Cer in human cancer cells MDA-MB-231. Since the Res biological activity in cancer cells is restricted by its photosensitivity and metabolic instability, the authors replaced the 3,5-hydroxy groups with much more stable methoxy groups, hence acquiring a compound with enhanced anti-proliferative activity. In addition, the stabilization with the stilbene double bond of Res by a naphthalene ring increases the molecular rigidity. This considerably improves the biological activity by means of Cer-mediated pro-apoptotic mechanism coupled to cleavage of PARP. 3.13. Silibinin Silibinin may be the most Cefadroxil (hydrate) Inhibitor active and main element (600 ) of silymarin, a standardized extract in the seeds of the milk thistle seeds (Silybum marianum). Other flavonolignans consist in silibinin, isosilibinin, silychristin, isosilychristin and silydianin. Silibinin is actually a mixture of two diastereomers, silybin A and silybin B, in approximately equimolar ratio [123]. It has been applied inside the prevention and therapy of viral hepatitis, cirrhosis triggered by alcohol abuse and liver damage caused by medications or industrial toxins, in classic and contemporary medicine. Silibinin effects are on account of cost-free radical trapping, prevention of lipid peroxidation, an increment of proapoptotic protein (Bax, p53), a decrement of anti-apoptotic proteins (Bcl-2 and Bcl-xL) and anti-cancer activity. Boojara et al. [124] investigated the effects of 4 silibinin derivatives which is silybin A, silybin B, 5-Propargylamino-ddUTP Data Sheet 3-O-galloyl-silybin A and 3-O-galloyl-silybin B on cell viability, caspase assessment, total Cer levels and Cer-metabolizing enzyme in Hep G2 hepatocarcinoma cell line. Exposure to silibinin isomers and gallate derivatives in human liver carcinoma cells resulted in increased Cer levels. Gallate derivatives had a stronger capability in Cer elevation in comparison with silybin A and B. The activity of aCDase, the enzyme involved inside the catabolism of Cer to Sph, was markedly inhibited by silybin B, 3-O-galloyl-silybin A and 3-O-galloyl-silybin B.