Antitumor effects of zoledronic acid in combination with histone deacetylase inhibitor valproic acid.

Abstract

e15158 Background: The established utilisation of bisphosphonates is the treatment of metastatic bone disease derived from several tumor types including prostate (PCa) and breast cancer. However, recently preclinical as well as clinical evidence support anti-tumor activities of these drugs in their own right. To probe into the molecular basis of such observations we treated PCa bone metastasis derived cell lines (VCaP, PC-3) and breast cancer cells (MCF-7) with zoledronic acid (ZA) and ZA in combination with valproic acid (VPA). HDAC-Inhibitor VPA according to our previous findings rectifies aberrant androgen receptor signalling and thus, implies an anti-androgen element in these treatments. Methods: PCa cells (VCaP, PC-3) and breast cancer cells (MCF-7) were treated with ZA (Zometa, Novartis) at 0, 5, 25 or 100µM or same ZA concentrations in combination with VPA (5mM). Tumor cell viability and proliferation were analysed by AlamarBlue- and BrdU-tests. Gene expression and PSA secretion was quantitated by real time RT-PCR and was further assessed with ELISA-kits, respectively. Results: In all cell types ZA has no impact on tumor cell viability or proliferation of its own exceeding the effects of VPA alone. Likewise, PSA secretion in VCaP cells is not further diminished in the combined ZA/VPA treatments. However, among a marked impact on cancer relevant gene expression protective elements such as vitamin D- and β-estrogen-receptor are up-regulated by ZA alone and in excess by the combined treatment. Other genes associated with protective features such as IGFBP-3, SOCS-3 and Se-BP-3 are up-regulated only by the ZA/VPA combination. Conclusions: We present molecular evidence for anti-tumor effects of zoledronic acid. Our data suggest the necessity of a concomitant anti-androgen treatment for maximal benefit. The genes addressed by such treatments are more associated with cancer prevention than immediate androgen signalling targets. Therefore, the main anti-tumor potential of ZA may emerge from an early onset of combined therapies to prevent bone metastases.