Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation
Article first published online: 24 JUN 2004
Volume 94, Issue 1, pages 164–170, July 2004
How to Cite
Coxon, J. P., Oades, G. M., Kirby, R. S. and Colston, K. W. (2004), Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation. BJU International, 94: 164–170. doi: 10.1111/j.1464-4096.2004.04831.x
- Issue published online: 24 JUN 2004
- Article first published online: 24 JUN 2004
- Accepted for publication 6 March 2004
- zoledronic acid;
- prostate cancer;
To investigate effects of zoledronic acid on apoptosis and adhesion to mineralized matrix in prostate cancer cells, to quantify these actions, and to elucidate some of the underlying molecular mechanisms, in terms of dependence on caspase activation and involvement of protein prenylation.
MATERIALS AND METHODS
DU145 and PC-3 prostate cancer cell lines were used; cells were treated with zoledronic acid, with or without several other reagents, to investigate its mechanism of action. Apoptosis was detected using a cell-death detection enzyme-linked immunosorbent assay. Adhesion was measured by seeding cells onto mineralized dentine inserts for 24 h, and counting cells after washing.
Apoptosis depended on time and dose; there was significant apoptosis with higher concentrations of zoledronic acid (100 µmol/L) after 24 h of exposure, and in DU145 cells with concentrations as low as 1 µmol/L after 72 h of exposure. The apoptotic effect was diminished by co-treating with a broad-spectrum caspase inhibitor, Z-VAD-FMK. Zoledronic acid at 1 µmol/L also significantly inhibited cell adhesion to the mineralized matrix. The lipid isoprenoid analogue geranylgeraniol reduced the apoptotic and anti-adhesive effects of zoledronic acid to a greater degree than farnesol. There was also apoptosis and inhibition of adhesion with direct inhibitors of prenylation, e.g. manumycin A and GGTI-298. C3 exoenzyme, an inhibitor of RhoA, inhibited adhesion but did not cause apoptosis.
Zoledronic acid induces apoptosis in prostate cancer cells via a caspase-dependent mechanism, and at concentrations as low as 1 µmol/L it also inhibits adhesion of cells to mineralized matrix. These effects appear to be exerted via inhibiting G-protein prenylation and in particular geranylgeranylation.