This effort led to the development of OSU-2S, which exhibits higher potency than FTY720 in suppressing HCC cell growth through PKCδ activation. In contrast to FTY720, OSU-2S was not phosphorylated by sphingosine kinase 2 (SphK2) in vitro, and did not cause S1P1 receptor internalization in HCC cells or T lymphocyte homing in immunocompetent mice. Although devoid of S1P1 receptor activity, OSU-2S exhibited higher in vitro antiproliferative efficacy

relative to FTY720 against HCC cells without cytotoxicity in normal hepatocytes. Several lines of pharmacological and molecular genetic evidence indicate that ROS–PKCδ–caspase-3 signaling underlies OSU-2S–mediated antitumor effects, and that differences in the antitumor activity between FTY720 and OSU-2S were attributable to SphK2-mediated phosphorylation of FTY720, which represents a metabolic inactivation of its ICG-001 antitumor activity. Finally, OSU-2S exhibited high in vivo potency in suppressing xenograft tumor growth in both ectopic and orthotopic models without overt toxicity. Conclusion: Using the molecular

platform of FTY720, we developed OSU-2S, a novel PKCδ-targeted antitumor agent, which is devoid of S1P1 receptor activity and is highly effective in suppressing HCC tumor growth in vivo. These findings suggest that OSU-2S has clinical value in therapeutic strategies check details for HCC and warrants continued investigation in this regard. (HEPATOLOGY 2011;) Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, and is expected to become more prevalent in the United States over the next decade due to the dramatic rise in the incidence of hepatitis MCE公司 C virus infection. A major challenge in the systemic treatment of HCC is cellular resistance to conventional cytotoxic agents, which may be attributed to the heterogeneity of genetic abnormalities acquired during the course of hepatocarcinogenesis.1 Consequently, targeting molecular defects that allow HCC cells to evade apoptosis

represents a viable strategy to improve patient outcome. Accordingly, a number of therapeutic agents targeting aberrant cellular growth and survival signaling pathways have been investigated for the treatment of HCC.2 Recently, sorafenib, a multikinase inhibitor, was approved for the treatment of advanced HCC.3 This therapy, however, only works in a subset of patients and is not curative, which underlies the urgency in identifying new therapies. FTY720, a synthetic sphingosine immunosuppressant, was recently approved for the treatment of relapsing multiple sclerosis.4 Its immunosuppressive effect is attributed to the ability of its phosphorylated metabolite (p-FTY720) to induce T lymphocyte homing by targeting sphingosine-1-phosphate (S1P) receptors.