Novel Tubulin Antagonist Pretubulysin Displays Antivascular Properties In Vitro and In Vivo
| Autor: | Verena K. Kretzschmann, Angelika M. Vollmar, Uli Kazmaier, Donata Gellrich, Angelika Ullrich, Robert Fürst, Stefan Zahler |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Pathology medicine.medical_specialty Time Factors RHOA Melanoma Experimental Tumor Cell Necrosis Neovascularization Physiologic Hamster Angiogenesis Inhibitors Soft Tissue Neoplasms Capillary Permeability Mice Necrosis Tubulin In vivo Cricetinae Stress Fibers Human Umbilical Vein Endothelial Cells medicine Animals Humans Myosin-Light-Chain Kinase Cells Cultured rho-Associated Kinases Matrigel Dose-Response Relationship Drug Mesocricetus Neovascularization Pathologic biology Actomyosin Tubulin Modulators Tumor Burden Mice Inbred C57BL Endothelial stem cell Intercellular Junctions Regional Blood Flow Cancer cell biology.protein Cancer research Female rhoA GTP-Binding Protein Cardiology and Cardiovascular Medicine Oligopeptides Ex vivo Signal Transduction |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 34:294-303 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.113.302155 |
| Popis: | Objective— Pretubulysin (PT) is a novel, synthetically accessible myxobacterial compound that acts as a tubulin-depolymerizing agent and inhibits cancer cell growth in vitro and in vivo. Moreover, PT was found to attenuate tumor angiogenesis. Here, we hypothesized that PT could exert antivascular activities on existing tumor vessels. Approach and Results— We aimed to characterize the antivascular effects of PT and to elucidate the underlying mechanisms in endothelial cells. In vitro, PT rapidly induced endothelial hyperpermeability and a concentration-dependent disassembly of established endothelial tubes on Matrigel and in an ex vivo aortic ring model. It disrupted endothelial cell junctions and triggered F-actin stress fiber formation and cell contraction by the RhoA/Rho-associated protein kinase pathway without causing cell death. In vivo, using a hamster dorsal skinfold chamber preparation, PT significantly decreased blood flow and vessel diameter in hamster A-Mel-3 amelanotic melanoma tumors but not in the neighboring healthy tissue. In a second tumor model using mice with subcutaneous murine B16 melanoma tumors, a single dose of PT (10 mg/kg) caused a shut down of tumor blood flow and a strong central tumor cell necrosis within 24 hours. Repeated PT administration significantly decelerates tumor growth and seems to be well tolerated. Conclusions— In summary, we could show for the first time that the antitumor effect of PT is, at least in part, mediated via its antivascular activities on existing tumor vessels. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|