Effects of combined treatment with Zometa and Taxol on endothelial cells in vitro

Background

Zoledronic acid (ZOL) (Novartis Pharma, Basel, Switzerland) is a N-containing bisphosphonate currently used in the treatment of osteoporosis and tumour-induced bone disease in a wide range of solid and haematologic malignancies. Previous studies have shown that ZOL interferes with endothelial cell (EC) function; however, little is known about the effect of ZOL on ECs of the microvascular network that resemble the tumour vasculature. Taxol (Bristol-Myers Squibb Company, New York, USA), also known as paclitaxel (PAC) (Sigma, UK), is a chemotherapeutic agent currently used in anticancer therapy. Previous studies on tumour cells have shown that it specifically interferes with microtubule assembly. Its antiangiogenic properties in vitro or in vivo remain unestablished. Combination treatments with ZOL and PAC have also been shown to have a synergistic effect on apoptosis in tumour cell lines.

Methods

We have investigated the effects of ZOL and PAC on ECs in vitro, both alone and in combination, therefore determining the effects on EC death and the ability of ECs to adhere onto membranes of various components of the extracellular matrix as well as on EC proliferation, migration and Rap1a prenylation.

Results

Human dermal microvascular ECs (HuDMECs) were treated with increasing doses of ZOL (0–50 μM) and PAC (0–10 nM) alone and in combination. ZOL affected EC proliferation (50 μM for 48 and 72 hours, P < 0.05), tube formation (50 μM for 24 hours, P < 0.05) and Rap1a prenylation. EC adhesion or apoptosis was not affected. PAC interfered with EC tube formation but not proliferation (24 and 48 hours). PAC also affected apoptosis; however, the exact level was dependent on the cell batch. Apoptosis was induced (50 μM ZOL and 2 nM PAC for 24 hours, P < 0.05) in cultures treated with ZOL and PAC together. Migration was inhibited at very low doses of PAC (500 pM) and 25 μM ZOL with combination treatment.

Conclusion

These data suggest that combinations of ZOL and PAC may have increased antiangiogenic effects compared with that caused by the single agents.