Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly.
Many conventional chemotherapeutics, such as the microtubule-stabilizing anticancer drug paclitaxel (Taxol), have been shown to have anti-angiogenic activity and clinical application of a continuous low dose of these agents has been suggested for cancer therapy. In this study, we show that paclitaxel selectively inhibits the proliferation of human endothelial cells (ECs) at ultra low concentrations (0.1-100 pM), with an IC50 = 0.1 pM, while it inhibits non-endothelial type human cells at 10(4) - to 10(5) -fold higher concentrations, with IC50 = 1-10 nM. The selectivity of paclitaxel inhibition of cell proliferation is also species specific, as mouse ECs are not sensitive to paclitaxel at ultra low concentrations. They are inhibited by higher concentrations of paclitaxel with IC50 = 1-10 nM. Inhibition of human ECs by paclitaxel at ultra low concentrations does not affect the cellular microtubule structure, and the treated cells do not show G2/M cell cycle arrest and apoptosis, suggesting a novel but as yet unidentified mechanism of action. In an in vitro angiogenesis assay, paclitaxel at ultra low concentrations blocks human ECs from forming sprouts and tubes in the three-dimensional fibrin matrix. In summary, paclitaxel selectively inhibits human EC proliferation and in vitro angiogenesis at low picomolar concentrations. The data support a clinical application of continuous ultra-low-dose paclitaxel to treat cancer.
Wang
Jieyi
J
Cancer Research, Global Pharmaceutical R & D, Abbott Laboratories, Abbott Park, IL 60064, USA. Jieyi.Wang@abbott.com
Lou
Pingping
P
Lesniewski
Rick
R
Henkin
Jack
J
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D017239:Paclitaxel / Q000008:administration & dosage*
D006131:Growth Inhibitors; D017239:Paclitaxel