Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Metronomic chemotherapy is the protracted, dense administration of low sub-toxic doses of chemotherapy, to inhibit tumor angiogenesis. Vinorelbine is an orally bioavailable vinca alkaloid shown to be useable for metronomic administration. In clinical trials, metronomic vinorelbine has been demonstrated to generate sustainable antitumor efficacy at low nanomolar (nM) concentrations with negligible toxicity. We sought to determine whether the clinically relevant metronomic concentration of vinorelbine is anti-angiogenic in vitro and whether hypoxia, often induced by anti-angiogenic therapy, modifies its effectiveness. We found that the metronomic concentration of 10 nM vinorelbine inhibited human umbilical vein endothelial cell (HUVEC) proliferation, migration, tube formation and sprouting. Severe hypoxia, did not affect the inhibitory effect of metronomic vinorelbine on migration, tube formation and sprouting. However, severe hypoxia reduced its anti-proliferative effect by decreasing its ability to induce G2/M block as it shifted the cell population to the G1 phase and decreased the fraction of the cells in the DNA synthesis S phase. Furthermore, the pro-apoptotic effects of 10 nM vinorelbine were also decreased. Metronomic vinorelbine decreased the Bcl-2/Bax ratio in normoxia whereas the ratio was reduced in severe hypoxia but unaltered by vinorelbine treatment. Akt signals to an anti-apoptotic pathway and we demonstrated that the Akt inhibitor V reversed the protective effect of severe hypoxia. Thus, we provide evidence for the anti-angiogenic basis of metronomic vinorelbine and we show that severe hypoxia mediates resistance to its anti-proliferative effect on endothelial cells. Akt warrants further investigation as a potential target to circumvent this hypoxic resistance.

Original publication

DOI

10.3892/ijo.2015.3059

Type

Journal article

Journal

Int J Oncol

Publication Date

08/2015

Volume

47

Pages

455 - 464

Keywords

Administration, Metronomic, Angiogenesis Inhibitors, Antineoplastic Agents, Phytogenic, Cell Hypoxia, Cell Movement, Cell Proliferation, Drug Resistance, Neoplasm, Human Umbilical Vein Endothelial Cells, Humans, In Vitro Techniques, Proto-Oncogene Proteins c-akt, Vinblastine, Vinorelbine