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.