Searchable abstracts of presentations at key conferences on calcified tissues
Bone Abstracts (2016) 5 P106 | DOI: 10.1530/boneabs.5.P106

ECTS2016 Poster Presentations Cancer and bone: basic, translational and clinical (37 abstracts)

The Rho GTPases RhoA and CDC42 mediate apoptosis by a combination of statins and zoledronic acid in human bone-seeking breast cancer cells

Andy Göbel 1 , Stefanie Thiele 1 , Andrew J Browne 1 , Martina Rauner 1 , Lorenz C Hofbauer 1, & Tilman D Rachner 1


1Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; 2German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.


Breast cancer is the most frequent malignancy in women and frequently results in osteolytic bone metastases. Amino-bisphosphonates are a standard bone protective therapy and, similarly to statins, inhibit the mevalonate pathway that is crucial for posttranslational protein modifications (farnesylation and geranylation). Direct anti-tumor effects of amino-bisphosphonates and statins have been suggested but high concentrations are necessary to achieve meaningful effects. Our study aimed to assess the potential of combining amino-bisphosphonates with statins to reach anti-tumor effects at lower doses.

We demonstrate that the expression levels of both targets of statins and amino-bisphosphonates, the 3-hydroxy-methyl-glutaryl-CoA reductase (HMGCR) and the farnesyl diphosphate synthase (FDPS), show a positive correlation in clinical samples of breast cancer (P≤0.0001) pointing to a potential benefit of simultaneously targeting both enzymes. Treating different osteotropic human cancer cell lines (MDA-MB-231, MDA-BONE, MDA-MET, MDA-453s, and PC3) with a combination of low concentrated statins (atorvastatin, simvastatin and rosuvastatin) and zoledronic acid resulted in significant anti-tumor-effects (50% reduction of cell vitality and fourfold induction of apoptosis; P<0.05). Apoptosis was the result of blocked geranylation rather than farnesylation. Rho GTPases like RhoA, Rac1, and CDC42 represent a major class of geranylated proteins. Surprisingly, the treatments with mevalonate pathway inhibitors, individually or in combination, caused an accumulation of GTP-bound RhoA and CDC42 but not of Rac1. Importantly the knockdown of RhoA and CDC42 prior to the treatment with simvastatin and zoledronic acid reduced the caspase 3/7 activation by up to 60% and the cleaved PARP accumulation by up to 80% in MDA-MB-231 human breast cancer cells (P<0.01). The observations point to a contribution of these Rho GTPases in the anti-tumor effects by statins and zoledronic acid.

Our results suggest the combination of statins and zoledronic acid as an effective approach for the adjuvant treatment of breast cancer.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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