Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2313-8. doi: 10.1073/pnas.0712198105. Epub 2008 Feb 11.

The marine lipopeptide somocystinamide A triggers apoptosis via caspase 8.

Author information

1
Department of Pathology, University of California at San Diego (UCSD) School of Medicine, and Moores UCSD Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093-0803, USA.

Abstract

Screening for novel anticancer drugs in chemical libraries isolated from marine organisms, we identified the lipopeptide somocystinamide A (ScA) as a pluripotent inhibitor of angiogenesis and tumor cell proliferation. The antiproliferative activity was largely attributable to induction of programmed cell death. Sensitivity to ScA was significantly increased among cells expressing caspase 8, whereas siRNA knockdown of caspase 8 increased survival after exposure to ScA. ScA rapidly and efficiently partitioned into liposomes while retaining full antiproliferative activity. Consistent with the induction of apoptosis via the lipid compartment, we noted accumulation and aggregation of ceramide in treated cells and subsequent colocalization with caspase 8. Angiogenic endothelial cells were extremely sensitive to ScA. Picomolar concentrations of ScA disrupted proliferation and endothelial tubule formation in vitro. Systemic treatment of zebrafish or local treatment of the chick chorioallantoic membrane with ScA resulted in dose-dependent inhibition of angiogenesis, whereas topical treatment blocked tumor growth among caspase-8-expressing tumors. Together, the results reveal an unexpected mechanism of action for this unique lipopeptide and suggest future development of this and similar agents as antiangiogenesis and anticancer drugs.

PMID:
18268346
PMCID:
PMC2268133
DOI:
10.1073/pnas.0712198105
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center