The bisphosphonate zoledronic acid and the cytotoxic drug doxorubicin induce synergistic levels of apoptosis in breast cancer cells. As zoledronic acid and doxorubicin have been shown to reduce cell invasion and migration, we have investigated if these drugs also act synergistically on breast cancer invasion in vitro. MCF7 cells were treated with 0.05 μM doxorubicin/4 h followed by 1 or 10 μM zoledronic acid/24 h (or the reverse sequence). To study invasion, MCF7 cells were either grown on Transwell membranes coated with Matrigel or in a 24-well plate. Cells were treated sequentially using the above drug combinations, prior to starting the invasion assays for 48 h. Cell growth and death were also assessed under the same conditions. We found that invasion of MCF7 cells treated with zoledronic acid and doxorubicin was significantly reduced when compared with control, but the effect was dependent on drug sequence. At 1 μM, zoledronic acid significantly reduced invasion only if cells were pre-treated with doxorubicin, but cell growth was unaffected. For 10 μM zoledronic acid, invasion was reduced when administered before or after the doxorubicin, but this dose of zoledronic acid caused a significant reduction in MCF7 growth. Apoptosis was not induced by any of the drug doses and combinations. We conclude that pre-treatment with 0.05 μM doxorubicin followed by 1 μM zoledronic acid reduces invasion when cells were grown on Matrigel. For 10 μM zoledronic acid, pre- or post-doxorubicin also reduces invasion, but for this combination inhibition of cell growth may contribute to the reduction in invasion observed.
aAcademic Unit of Clinical Oncology, Genomic Medicine, Medical School, University of Sheffield, Sheffield, UK
Sponsorship: Weston Park Cancer Appeal has supported this work. Novartis kindly donated the zoledronic acid.
Correspondence to J. K. L. Woodward, Academic Unit of Clinical Oncology, Division of Genomic Medicine, D Floor, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
Tel: +44 114 271 2375; fax: +44 114 271 3314;
Received 28 May 2005 Accepted 14 June 2005