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 microM
doxorubicin/4 h followed by 1 or 10 microM
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 microM,
zoledronic acid significantly reduced invasion only if cells were pre-treated with
doxorubicin, but cell growth was unaffected. For 10 microM
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 microM
doxorubicin followed by 1 microM
zoledronic acid reduces invasion when cells were grown on
Matrigel. For 10 microM
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.