title: The cell cycle arrest and the anti-invasive effects of nitrogen-containing bisphosphonates are not mediated by DBF4 in breast cancer cells.
abstract: Recent work has shown that a DBF4 analog in yeast may be a target of nitrogen-containing bisphosphonates. DBF4 is an essential protein kinase required for DNA replication from primary eukaryotes to humans and appears to play a critical role in the S-phase checkpoint. It is also required for cell migration and cell surface adhesion. The effects of Pamidronate, risedronate, or zoledronate on cell viability and DBF4 expression were measured via MTT assays and western blotting. In addition, FACS cell cycle analyses and invasion assays were conducted in cells in the presence of nitrogen-containing bisphosphonates to identify any correlations between DBF4 expression and S-phase arrest or anti-invasive effects of the bisphosphonates. Zoledronate transiently down-regulated DBF4 expression in all three cell lines in the first 24 h of the experiment, but after 72 h, DBF4 expression returned to the control levels in all treated cells. Following treatment of the tumor cells with the bisphosphonates, the number of cells in S-phase was increased. Pamidronate and zoledronate showed anti-invasive effects in BT20 cells. The anti-invasive effects of pamidronate, risedronate and zoledronate appeared after 48 h of exposure. In MDA-MB231 cells a reduction of invasiveness was only observed after 72 h of the pamidronate exposure. We finally concluded that the anti-invasive and cell cycle arrest-inducing effects of nitrogen-containing bisphosphonates are not DBF4 mediated, and other mediators are therefore needed to explain the observed complex behaviors.
authors.affiliation: Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Iran.
authors.forename: Mahdieh
authors.initials: M
authors.lastname: Mansouri
authors.affiliation: Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Iran; Institute of Pathology, Charité Campus Mitte, University Medicine Berlin, Berlin, Germany.
authors.forename: Seyed Abbas
authors.initials: SA
authors.lastname: Mirzaei
authors.affiliation: Institute of Pathology, Charité Campus Mitte, University Medicine Berlin, Berlin, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Lage
authors.affiliation: Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Iran.
authors.forename: Seyyedeh Soghra
authors.initials: SS
authors.lastname: Mousavi
authors.affiliation: Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Iran; Institute of Pathology, Charité Campus Mitte, University Medicine Berlin, Berlin, Germany. Electronic address: elahian@zums.ac.ir.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Elahian
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009361:Neoplasm Invasiveness; D000077268:Pamidronate; D000068296:Risedronic Acid; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C485678:DBF4 protein, human; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D000068296:Risedronic Acid; D012968:Etidronic Acid; D000077268:Pamidronate
keywords: Bisphosphonates; Cell cycle; DBF4; Invasion assay; Risedronate; Zoledronate