Article first published online: 2 MAY 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 53, Issue 6, pages 1943–1958, June 2011
How to Cite
Omar, H. A., Chou, C.-C., Berman-Booty, L. D., Ma, Y., Hung, J.-H., Wang, D., Kogure, T., Patel, T., Terracciano, L., Muthusamy, N., Byrd, J. C., Kulp, S. K. and Chen, C.-S. (2011), Antitumor effects of OSU-2S, a nonimmunosuppressive analogue of FTY720, in hepatocellular carcinoma. Hepatology, 53: 1943–1958. doi: 10.1002/hep.24293
Potential conflict of interest: Nothing to report.
Supported by Public Health Service Grants R21 CA133710 and R01 CA112250 from the National Cancer Institute of the National Institutes of Health (to C.S.C.), by the Lucius A. Wing Chair Fund of The Ohio State University Medical Center (to C.S.C.), and a Specialized Center of Research grant from the Leukemia and Lymphoma Society (to C.S.C., N.M., and J.C.B.).
- Issue published online: 25 MAY 2011
- Article first published online: 2 MAY 2011
- Accepted manuscript online: 9 MAR 2011 12:56PM EST
- Manuscript Accepted: 1 MAR 2011
- Manuscript Received: 21 SEP 2010
Accumulating evidence suggests the therapeutic potential of the immunosuppressive agent FTY720 (fingolimod) in hepatocellular carcinoma (HCC). Based on our previous finding that FTY720 mediates apoptosis in HCC cells by activating reactive oxygen species (ROS)–protein kinase Cδ (PKCδ) signaling independent of effects on sphingosine-1-phosphate (S1P) receptors, we embarked on the pharmacological exploitation of FTY720 to develop a nonimmunosuppressive analogue with antitumor activity. 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 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 for HCC and warrants continued investigation in this regard. (HEPATOLOGY 2011;)