Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells

Research output: Contribution to journalResearch articleContributedpeer-review



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.


Original languageEnglish
Pages (from-to)162-171
Number of pages10
JournalCancer letters
Issue number1
Publication statusPublished - 28 May 2016

External IDs

Scopus 84960448650
PubMed 26968247
ORCID /0000-0001-9345-026X/work/150883243
ORCID /0000-0002-8691-8423/work/150882250


Sustainable Development Goals


  • Antineoplastic Agents/pharmacology, Apoptosis, Atorvastatin/pharmacology, Biosynthetic Pathways/drug effects, Breast Neoplasms/drug therapy, Caspase 3/metabolism, Caspase 7/metabolism, Cell Line, Tumor, Cell Survival, Diphosphonates/pharmacology, Drug Synergism, Enzyme Activation, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology, Imidazoles/pharmacology, Mevalonic Acid/metabolism, Zoledronic Acid, rho GTP-Binding Proteins/metabolism