Adhesion to Unmineralized and Mineralized Bone Extracellular Bisphosphonates Inhibit Prostate and Breast Carcinoma Cell

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 unmlnerallzed and mineralized osteoblas tic extracellular matrices in a dose-dependent manner. In contrast, HP 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 (antire sorptlve active pyrldinium analogue ofrisedronate) > pamidronate > do dronate. HP did not affect [3H]thymldineIncorporationby tumor cells, as assessed by a mitogenesls assay, indicating that HP did not exert any cytotoxlc effect at concentrations used to Inhibit tumor cell adhesion. NE-58051, the Inactive pyrldylpropylldene 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, HP recognition by tumor cells did not mOdUlatecell surface Integrin expression. In conclu slon, our results provide evidence for a direct cellular effect of BP In preventing tumor cell adhesion to bone, suggesting that HPs may be useful agents for the prophylactic treatment of patients with cancer that Is known to preferentially metastasize to bone.