title: Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells.
abstract: The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. However, the long-term effects of either MTD or LDM chemotherapy on vascular endothelial cells have never been investigated. Here, we demonstrated that repeated exposure to MTD and LDM chemotherapy differentially impact on the angiogenic potential and chemosensitivity of immortalized endothelial cells. Repeated MTD vinblastine treatment of vascular endothelial cells led to an increased proliferation rate and resistance to paclitaxel. In contrast, repeated LDM treatment with vinblastine or etoposide impaired the angiogenic potential of endothelial cells and increased their chemosensitivity. This effect was associated with a significant decrease in βII- and βIII-tubulin expression. Functional analysis using siRNA showed that silencing the expression of βIII-tubulin in endothelial cells significantly decreased their capacity to form vascular structures and increased their sensitivity to the anti-angiogenic and vascular-disrupting effects of chemotherapy, whereas silencing βII-tubulin expression had no effect. Collectively our results show that LDM chemotherapy impairs the angiogenic potential of endothelial cells while increasing their chemosensitivity-an effect at least in part mediated by the down-regulation of βIII-tubulin expression. Furthermore, our study suggests that βIII-tubulin represents an attractive therapeutic target to increase the anti-angiogenic effects of chemotherapy and overall anti-tumour efficacy.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, PO Box 81, Randwick, NSW, 2031, Australia.
authors.forename: Eddy
authors.initials: E
authors.lastname: Pasquier
authors.forename: Maria-Pia
authors.initials: MP
authors.lastname: Tuset
authors.forename: Janine
authors.initials: J
authors.lastname: Street
authors.forename: Snega
authors.initials: S
authors.lastname: Sinnappan
authors.forename: Karen L
authors.initials: KL
authors.lastname: MacKenzie
authors.forename: Diane
authors.initials: D
authors.lastname: Braguer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andre
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D002461:Cell Line, Transformed; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D034741:RNA, Small Interfering; D014404:Tubulin