The body weight in this study did not differ in placebo vs. D-PDMP�Ctreated mice. The tumor weight decreased approximately 50% in 3 MPK and 10 MPK fed mice compared to placebo. However, when mice were fed higher amounts of D-PDMP; 25 and 50 MPK, it did not further reduce tumor volume. In a previous study, it was shown that the t1/2 of D-PDMP in mice blood is,50 min. Consequently, it is feasible that beyond a threshold of 10 MPK, most of this compound is rapidly removed by excretion and therefore further reduction in tumor volume was not observed. Previously, D-PDMP has been used extensively to examine the role of glycosphingolipid and related glycosytransferases in arterial smooth muscle cell proliferation, wound healing, osteoclastogenesis, polycystic kidney disease, elasticity, respiratory diseases, glioblastoma research cholesterol efflux, inflammation in vitro and in vivo, shear stress, and A beta secretion in neuroblasotma cells. Covalent protein lipidation is an important protein modification in eukaryotic cells that enables the reversible association of hundreds of proteins with the membrane. Protein lipid transferases, prenyl-transferases, myristoyl-and palmitoyl-transferases attach lipid moieties in particular to signaling proteins. Most of these transferases are well established drug targets in a number of diseases, most notably cancer. They may be regarded as surrogate targets, as their protein substrates such as for instance Ras-superfamily proteins are very difficult to target directly. Inhibition of lipid transferases renders their protein substrates cytoplasmic thereby dramatically reducing their biological activity as exemplified by the important 485-49-4 supplier oncoproteins Src-and Ras. It has been shown that of membrane associated Ras SPDP molecules are concentrated in signaling packages, termed nanoclusters that contain Ras molecules. Nanoclustering is essential for Ras activity and disruption of clustering leads to a reduction in Ras activity and prevents its robust biological signaling. These experimental data are supported by computational simulations, which suggest that lipidanchors of Ras spontaneously organize into membrane nanocluster in mammalian cells. Due to the high local protein density, nanoclustering can be detected by FRET, if the nanoclustered polypeptides are fused to FRET fluorophores, such as mCFP and mCit. While there are already numerous inhibitors for the Ras modifying farnesyltransferase and geranylgeranyltransferase in preclinical and clinical trials, there is a paucity of potent and specific inhibitors of other lipid transferases, including Nmyristoyltransferases.
