We recently demonstrated original anti-
tumor effects of
zoledronic acid (Zol) on
osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by
osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2)
osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of
osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-
cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of
clodronate and
pamidronate evidenced that this drug resistance was restricted to the
nitrogen-containing
bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl
diphos-phate synthase (FPPS) also observed in human
osteosarcoma samples. The transfection of Zol-resistant cells with FPPS
siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of
osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of
drug metabolic resistance.