title: Pseudolarix acid B, a new tubulin-binding agent, inhibits angiogenesis by interacting with a novel binding site on tubulin.
abstract: Tubulin-binding agents have received considerable interest as potential tumor-selective angiogenesis-targeting drugs. Herein, we report that pseudolarix acid B (PAB), isolated from the traditional Chinese medicinal plant Pseudolarix kaempferi Gordon, is a tubulin-binding agent. We further demonstrate that PAB significantly and dose-dependently inhibits proliferation, migration, and tube formation by human microvessel enthothelial cells. It is noteworthy that PAB eliminated newly formed endothelial tubes and microvessels both in vitro and in vivo. In addition, PAB dramatically arrested the cell cycle at G2/M phase. PAB also induced endothelial cell retraction, intercellular gap formation, and promoted actin stress fiber formation in conjunction with disruption of the tubulin and actin cytoskeletons. All of these effects occurred at noncytotoxic concentrations of PAB. We found that these effects of PAB are attributable to depolymerization of tubulin by direct interaction with a distinct binding site on tubulin compared with those of colchicine and vinblastine. Taken together, these findings show that PAB is a candidate antiangiogenic agent for use in cancer therapy, and they provide proof of principle for targeting this novel binding site on tubulin as a new strategy for treating cancer.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Yun-Guang
authors.initials: YG
authors.lastname: Tong
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Zhang
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Geng
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Yue
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Xin
authors.forename: Fang
authors.initials: F
authors.lastname: Tian
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Lin-Jiang
authors.initials: LJ
authors.lastname: Tong
authors.forename: Mei-Hong
authors.initials: MH
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Li
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000254:growth & development; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D002942:Circular Dichroism; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D004224:Diterpenes; D014404:Tubulin; C058391:pseudolaric acid B