title: Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells.
abstract: Amino-bisphosphonates are antiresorptive drugs for the treatment of osteolytic bone metastases, which are frequently caused by breast and other solid tumors. Like statins, amino-bisphosphonates inhibit the mevalonate pathway. Direct anti-tumor effects of amino-bisphosphonates and statins have been proposed, although high concentrations are required to achieve these effects. Here, we demonstrate that the treatment of different human breast cancer cell lines (MDA-MB-231, MDA-Bone, and MDA-Met) by combined inhibition of the mevalonate pathway using statins and zoledronic acid at the same time significantly reduces the concentrations required to achieve a meaningful anti-tumor effect over a single agent approach (50% reduction of cell vitality and 4-fold increase of apoptosis; p < 0.05). The effects were mediated by suppressed protein geranylation that caused an accumulation of GTP-bound RhoA and CDC42. Importantly, the knockdown of both proteins prior to mevalonate pathway inhibition reduced apoptosis by up to 65% (p < 0.01), indicating the accumulation of the GTP-bound GTPases as the mediator of apoptosis. Our results point to effective anti-tumor effects in breast cancer by the combination of statins and zoledronic acid and warrant further validation in preclinical settings.
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andy
authors.initials: A
authors.lastname: Göbel
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Browne
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Zinna
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.affiliation: Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany. Electronic address: Tilman.Rachner@uniklinikum-dresden.de.
authors.forename: Tilman D
authors.initials: TD
authors.lastname: Rachner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000069059:Atorvastatin / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004164:Diphosphonates / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D000077211:Zoledronic Acid; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D000077211:Zoledronic Acid; D000069059:Atorvastatin; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid
keywords: Apoptosis; Breast cancer; Mevalonate pathway; Rho-GTPases; Statins; Zoledronic acid