Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway.
Angiogenesis is a critical event in tumor growth and metastasis, which can be inhibited by conventional anticancer drugs such as the microtubule-damaging agent paclitaxel (Taxol). In this study, we investigate the mechanism of action of paclitaxel on human endothelial cells. We characterize two distinct effects of paclitaxel on human umbilical vein endothelial cell and human microvascular endothelial cell-1 proliferation according to drug concentration: a cytostatic effect at low concentrations and a cytotoxic effect at concentrations > or =10 nmol/L. The cytotoxic effect involves signaling pathways similar to those described in tumor cells (i.e., microtubule network disturbance, G(2)-M arrest, increase in Bax/Bcl-2 ratio, and mitochondria permeabilization) that result in apoptosis. In sharp contrast, the cytostatic effect involves an inhibition of endothelial cell proliferation without apoptosis induction and without any structural modification of the microtubule network. This cytostatic effect is due to a slowing of the cell cycle rather than to an arrest in a specific phase of the cell cycle. In addition, paclitaxel, at cytostatic concentrations, early initiates an apoptotic signaling pathway associated with increases in the mitochondrial reducing potential, mitochondrial membrane potential, p53 expression, and Bax/Bcl-2 ratio. However, this apoptotic pathway is stopped upstream of mitochondria permeabilization and it does not lead to endothelial cell death. Finally, we found that paclitaxel inhibits endothelial cell morphogenesis on Matrigel at all tested concentrations. In conclusion, we describe the mechanism of action of low concentrations of paclitaxel related to the antiangiogenic properties of this drug.
FRE-Centre National de la Recherche Scientifique 2737, ISPDCT, Université de la Méditerranée, UFR Pharmacie, 27 Bd Jean Moulin, 13005 Marseille, France.
Eddy
E
Pasquier
Manon
M
Carré
Bertrand
B
Pourroy
Laurence
L
Camoin
Ouafa
O
Rebaï
Claudette
C
Briand
Diane
D
Braguer
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002455:Cell Division; D049109:Cell Proliferation; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016195:G2 Phase; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology; D008564:Membrane Potentials; D008833:Microcirculation / Q000166:cytology; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D011509:Proteoglycans / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013997:Time Factors; D051028:bcl-2-Associated X Protein
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C059485:matrigel; D003094:Collagen; D017239:Paclitaxel