ABSTRACT
EDSM, an endostatin-derived synthetic polypeptide, contains the amino acids 6-48 of endostatin from its N-terminus, which could inhibit human umbilical vein endothelial cell (HUVEC) migration and tumor growth. To increase the targeted delivery of EDSM to tumors and further enhance its antiangiogenic activity, the RGD sequence (Arg-Gly-Asp) was introduced into EDSM and two peptides were obtained: EDSM-X with RGD on the N-terminus of EDSM and EDSM-Y with RGD on the C-terminus. Both modified peptides showed a significant antiangiogenic activity in the HUVEC migration assay, the HUVEC tube formation assay, and the murine aortic ring formation assay in vitro. In agreement with the in-vitro data, EDSM-X and EDSM-Y also showed a significant antitumor activity in vivo. From the cell adhesion assay, it was confirmed that the molecular target of the modified peptides on HUVECs was integrin αvß3, rather than integrin α5ß1. Furthermore, EDSM-Y exhibited more potent antiangiogenic activity and antitumor activity than EDSM-X in vitro and in vivo, and this phenomenon was attributed to the difference in the two modified peptides in their three-dimensional structure modeling and their molecular dockings with integrin αvß3.
Subject(s)
Antineoplastic Agents/pharmacology , Endostatins/pharmacology , Melanoma, Experimental/drug therapy , Neovascularization, Pathologic/drug therapy , Animals , Antineoplastic Agents/chemistry , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Cell Adhesion/drug effects , Cell Movement/drug effects , Drug Delivery Systems , Endostatins/chemistry , Female , Human Umbilical Vein Endothelial Cells , Humans , Integrin alphaVbeta3/metabolism , Melanoma, Experimental/blood supply , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Oligopeptides/chemistry , Rats, Sprague-DawleyABSTRACT
The chemical components of the volatiles from the leaves and branches of Larix principis-rupprechtii were analyzed by GC-MS, with their allelopathic effects on the seed germination and growth of L. principis-rupprechtii itself investigated. The results indicated that the volatiles contained 20 major components, and the main constituents were terpenes and their oxidized derivatives, in which, there were 5 monoterpenes and 12 sesquiterpenes. The volatiles from the leaves and branches of L. principis-rupprechtii had significant inhibitory effects on the germination rate, germination speed index, radical length, hypocotyl length, and fresh mass of L. principis-rupprechtii itself, indicating that these volatiles contained potential allelochemicals, which might be related to the higher contents of terpenes and their oxidized derivatives. The allelopathic effects of the volatiles affected the regeneration of L. principis-rupprechtii, which should be a reason for the degeneration of artificial pure L. principis-rupprechti forest.
