The molecular mechanisms by which
tumor cells induce osteolytic
metastases are likely to involve
tumor cell adhesion to bone as well as the release of soluble mediators from
tumor cells that stimulate osteoclast-mediated
bone resorption.
Bisphosphonates (BPs) are powerful inhibitors of the osteoclast activity and are, therefore, used in the treatment of
cancer-associated osteolytic
metastases. Here, we investigated the effect of BPs on breast and prostate
carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. BP pretreatment of
tumor cells inhibited
tumor cell adhesion to unmineralized and mineralized osteoblastic extracellular matrices in a dose-dependent manner. In contrast, BP did not affect adhesion of normal cells (fibroblasts) to extracellular matrices. The order of potency for four BPs in inhibiting
tumor cell adhesion to extracellular matrices was found to be:
ibandronate >
NE-10244 (antiresorptive active pyridinium analogue of
risedronate) >
pamidronate >
clodronate. BP did not affect [3H]
thymidine incorporation by
tumor cells, as assessed by a mitogenesis assay, indicating that BP did not exert any cytotoxic effect at concentrations used to inhibit
tumor cell adhesion.
NE-58051, the inactive pyridylpropylidene analogue of
risedronate, had no inhibitory effect on
tumor cell adhesion compared to that observed with its active counterpart
NE-10244, suggesting that the mechanism of action of BP on
tumor cells involved a stereospecific recognition step. Although
integrins mediate cell-matrix interactions, BP recognition by
tumor cells did not modulate cell surface
integrin expression. In conclusion, our results provide evidence for a direct cellular effect of BP in preventing
tumor cell adhesion to bone, suggesting that BPs may be useful agents for the prophylactic treatment of patients with
cancer that is known to preferentially metastasize to bone.