Regulation of VEGF by mevalonate pathway inhibition in breast cancer

Publication date: September 2013 Source:Journal of Bone Oncology, Volume 2, Issue 3 Author(s): Tilman D. Rachner , Andy Göbel , Maria Junker , Josefa Hötzel , Peggy Benad-Mehner , Peyman Hadji , Lorenz C. Hofbauer Aminobisphosphonates are used for the treatment of benign and malignant bone disorders. As inhibitors of the mevalonate pathway they exert direct anti-tumor effects in vitro and in preclinical models of bone metastases. Bisphosphonates are thought to have an anti-angiogenic activity as decreased levels of VEGF have been reported in some, although not all patients, following treatment with bisphosphonates. Direct effects of bisphosphonates on tumor derived VEGF have not been examined in detail. We therefore investigated VEGF expression in breast cancer cell lines following mevalonate pathway inhibition. Treatment of cell lines with increasing doses of zoledronic acid and atorvastatin resulted in increased levels of VEGF production. Similar results were seen with the geranylgeranyltransferase I inhibitor GGTI-298. The induction of VEGF was reversed by the supplementation of geranylgeranyl pyrophosphate but not by farnesyl pyrophosphate indicating that this effect is mediated by inhibited geranylgeranylation. Previous reports have reported decreased VEGF levels in patients following BP treatment in vivo. We assessed VEGF levels in patients with non-metastatic breast cancer following repeated treatment with zoledronic acid. In contrast to our in vitro findi...
Source: Journal of Bone Oncology - Category: Cancer & Oncology Source Type: research