title: Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro.
abstract: 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.
authors.affiliation: Academic Unit of Clinical Oncology, Genomic Medicine, Medical School, University of Sheffield, UK. j.k.woodward@sheffield.ac.uk
authors.forename: Julia K L
authors.initials: JK
authors.lastname: Woodward
authors.forename: Helen L
authors.initials: HL
authors.lastname: Neville-Webbe
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004164:Diphosphonates / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use*; D004338:Drug Combinations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007797:Laminin / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D011509:Proteoglycans / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D000903:Antibiotics, Antineoplastic; D004164:Diphosphonates; D004338:Drug Combinations; D007093:Imidazoles; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D000077211:Zoledronic Acid; D004317:Doxorubicin; D003094:Collagen