title: Peloruside A is a microtubule-stabilizing agent with exceptional anti-migratory properties in human endothelial cells.
abstract: Peloruside A is a novel antimitotic drug originally isolated from the marine sponge Mycale hentschieli. Previous studies showed that peloruside A stabilizes microtubules by binding to a site on tubulin distinct from paclitaxel, another microtubule stabilizing drug. Peloruside A blocks mitosis, but little is known about the effects on other cellular activities. Here we report that peloruside A is the most potent microtubule inhibitor yet tested for its ability to block endothelial cell migration. Quantitative analysis indicated that it inhibits microtubule dynamics and endothelial cell migration at 1/200(th) of the concentration needed to inhibit cell division (the cytotoxic concentration), indicating that it could potentially have a large margin of safety when used to specifically target angiogenesis. By comparison, paclitaxel, a well-known cancer therapeutic drug, suppresses cell migration at 1/13(th) of its cytotoxic concentration; and vinblastine suppresses cell migration at just slightly below its cytotoxic antimitotic concentration. Thus, different microtubule targeted drugs have varying relative potencies for inhibition of cell migration versus cell division. The results suggest that peloruside A may be an especially useful agent for anti-angiogenesis therapy and point to the likelihood that other antimitotic drugs might be found with an even larger potential margin of safety.
authors.affiliation: Department of Microbiology Immunology and Infectious Diseases, University of Calgary.
authors.forename: Anutosh
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Medical School.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cabral
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hailing
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary.
authors.forename: Kamala D
authors.initials: KD
authors.lastname: Patel
keywords: angiogenesis; cell migration; endothelial cells; microtubule dynamics