Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 34, Issue 2, Pages 294-303Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.113.302155
Keywords
drug research; endothelial cells; neoplasms; pharmacology
Categories
Funding
- German Research Foundation [DFG FOR 1406 FU 691/9-1]
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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.
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