Abstract A108: Targeting sphingolipid metabolism and metastasis with motuporamine derivatives

Abstract

Abstract The purpose of this research is to develop non-toxic antimetastatic agents for use in the treatment of metastatic pancreatic cancers. Dihydromotuporamine C (1) and related motuporamines were previously isolated from the sea sponge Xestospongia exigua found off the coast of Motupore island, New Guinea. The motuporamine structure contains a large heterocycle with an appended polyamine chain. These are of biological interest due to their potent anti-migration and anti-angiogenic properties. Previous work demonstrated key structural features (i.e., saturated 15-membered heterocycle and norspermidine) necessary for their antimetastatic activity. Genetic studies in yeast suggested that these compounds target sphingolipid metabolism. In this report, a series of carbocycle-polyamine conjugates were explored to find compounds with improved properties. Of this panel, (N1-(3-aminopropyl)-N3-(cyclopentadecylmethyl)propane-1,3-diamine 2) was discovered which had a two-fold increase in anti-migration potency and was 133-fold less toxic than 1. Several experimental procedures were used to investigate perturbations in sphingolipid metabolism. Significant changes in specific ceramide populations (N16:0 and N22:1) were noted in human L3.6pl metastatic pancreatic cancer cells treated with 1, but not with derivative 2 (which was similar to the untreated control). Both 1 and 2 gave increased levels of low molecular weight sphingomyelins and inhibited cell migration in vitro. A mouse model using metastatic human L3.6pl pancreatic cancer cells demonstrated significant reduction in L3.6pl liver metastases for mice treated with the new derivative 2 compared with the parent compound 1. In summary, alterations in the N16:0/N22:1 ceramide ratio provided a potential explanation for the toxicity of 1. Significantly increased levels of low molecular weight sphingomyelins in cells treated with either 1 or 2 suggested that they potentially target sphingomyelin synthase (as agonists) or sphingomyelinase enzymes (as inhibitors). We speculate that these increased levels of sphingomyelin may inhibit metastatic pathways associated with CXCR4 signaling; a pathway with known sensitivity to sphingomyelin. In conclusion, this report describes for the first time how compounds of this type alter chain-length specific ceramide and sphingomyelin populations in metastatic pancreatic cancer cells and suggests a novel mechanism for how they inhibit pancreatic cell metastasis.