Linked Life Data

21391227

Source:http://linkedlifedata.com/resource/pubmed/id/21391227

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2011-5-27
pubmed:abstractText
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 C? (PKC?) 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 PKC? 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-PKC?-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 PKC?-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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1527-3350
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 American Association for the Study of Liver Diseases.
pubmed:issnType
Electronic
pubmed:volume
53
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1943-58
pubmed:dateRevised
2011-9-26
pubmed:meshHeading
pubmed-meshheading:21391227-Animals, pubmed-meshheading:21391227-Antineoplastic Agents, pubmed-meshheading:21391227-Carcinoma, Hepatocellular, pubmed-meshheading:21391227-Caspase 3, pubmed-meshheading:21391227-Cell Line, Tumor, pubmed-meshheading:21391227-Cell Proliferation, pubmed-meshheading:21391227-Cells, Cultured, pubmed-meshheading:21391227-Hepatocytes, pubmed-meshheading:21391227-Humans, pubmed-meshheading:21391227-Liver Neoplasms, pubmed-meshheading:21391227-Mice, pubmed-meshheading:21391227-Mice, Nude, pubmed-meshheading:21391227-Propylene Glycols, pubmed-meshheading:21391227-Protein Kinase C-delta, pubmed-meshheading:21391227-Reactive Oxygen Species, pubmed-meshheading:21391227-Signal Transduction, pubmed-meshheading:21391227-Sphingosine, pubmed-meshheading:21391227-Xenograft Model Antitumor Assays
pubmed:year
2011
pubmed:articleTitle
Antitumor effects of OSU-2S, a nonimmunosuppressive analogue of FTY720, in hepatocellular carcinoma.
pubmed:affiliation
Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA. chen.844@osu.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural