Zoledronic acid and atorvastatin inhibit αvβ3-mediated adhesion of breast cancer cells

Abstract

Bone metastases represent common long term complications of patients with breast cancer. Zoledronic acid, an amino-bisphosphonate and mevalonate pathway inhibitor, is an established agent for the treatment of bone metastases. Direct antitumor effects of zoledronic acid have been proposed in breast cancer. Statins are another group of mevalonate pathway inhibitors that have been repeatedly discussed for potential anti-tumor activity. In this study, we tested the hypothesis, whether these agents regulate adhesion of breast cancer cells to extracellular matrix components. Treatment of breast cancer cells with zoledronic acid and atorvastatin, significantly impaired MDA-MB-231 breast cancer cell adhesion on the αvβ3 ligands gelatin and vitronectin, but had no effect on collagen type 1 (α2β1-ligand) and fibronectin (α5β1-ligand). Anti-adhesive effects of zoledronic acid were fully reversed by geranylgeranyl pyrophosphate (GGPP), but not by farnesylpyrophosphate (FPP). Furthermore, effects of zoledronic acid and atorvastatin were mimicked by a specific inhibitor of geranylgeranylation GGTI-298. Functional (using integrin array) and quantitative (using FACS) integrin analyses on MDA-231 cells following zoledronic acid exposure revealed decreased levels of αv and αvβ3 expression. In addition to its effects on integrin mediated adhesion of breast cancer cells, the presence of zoledronic acid caused pronounced morphological changes in MDA-231 cells as seen by F-actin and vinculin rearrangement. Furthermore, phosphorylation of the focal adhesion kinase was inhibited by zoledronic acid. In both cases, changes were fully reversed by GGPP. These results emphasize the role of mevalonate pathway mediated impairment of geranylgeranylation in the anti-adhesive effects of zoledronic acid in breast cancer cells.

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

“…Significantly impairs cancer cell adhesion on alphavbeta3 expression (193) Zoledronic acid + paclitaxel FPPS Breast cancer Has synergistic effect on tumor cell number and apoptosis (194) Zoledronic acid + atorvastatin FPPS, HMGCR Breast cancer Combined inhibition achieves a meaningful anti-tumor effect by suppressed protein geranylation (195) Zoledronic acid + gefitinib FPPS, EGFR Non-small cell lung cancer Increases the antitumor effect of gefitinib by inhibiting STAT3 expression (196) lung cancer by decreasing proliferative and migratory capacity and inducing apoptosis, which is mediated by SphK1 (160), COX-2/PPARγ (161), TGF-β RII/Erk (162), and other key pathways (204). Lung cancer cells metastasize to the bone and release RANKL, IL-6, and other factors to stimulate osteoclasts, which can be inhibited by fluvastatin through autophagy induction and osteoclastogenesis (163)(164)(165).…”

“…Another N-BP, YM529, also exerts anti-tumor effects against various types of cancer cells, including PCa, NSCLC, and bladder cancer, by various mechanisms such as CXCR-4-induced invasion ( 189 ), down-regulation of Erk1/2 phosphorylation ( 190 ), and inhibition of Rap1A prenylation ( 191 ). In addition, N-BPs have been used in combination with chemotherapy, statins or enzyme inhibitors to achieve additive or synergistic effects by diverse mechanisms, including a reduction in protein prenylation, impairment of geranylgeranylation or inhibition of STAT3 in prostate ( 192 ), breast ( 193 – 195 ), and lung ( 196 ) cancers. The effects of FPPS inhibitors such as ZOL and YM529 alone and in combination with other drugs targeting multiple signaling pathways in cancer cell and xenograft models are summarized in Table 2 .…”

P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer

“…RNA was isolated and RT and real-time PCR was performed as previously described [14]. Briefly, RNA was isolated using the HighPure RNA extraction kit from Roche according to the manufacturer's protocol.…”

“…Western blot analyses were performed as previously described [14]. Cells were washed and scraped in a lysis buffer and quantified.…”

Chemical approaches to inhibitors of isoprenoid biosynthesis: targeting farnesyl and geranylgeranyl pyrophosphate synthases

“…25 FPPS has been identied as a target for a series of drugs acting as anticancer, antimicrobial and antiparasitic agents. 26 In particular, human FPPS is a drug target for cancer, 27,28 osteoporosis and related diseases, [29][30][31] Paget's disease, 32,33 metastatic diseases, 34 and cardiovascular disorders. 35 Inhibition of human GGPPS has been reported as a new route to bone antiresorption 36 and the same enzyme from Plasmodium has been identied as a target against malaria.…”