Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases

The molecular mechanisms by which tumor cells metastasize to bone are likel y to involve invasion, cell adhesion to bone, and the release of soluble me diators 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 patients with osteolytic metas tases, However, an added beneficial effect of BPs may be direct antitumor a ctivity, We previously reported that BPs inhibit breast and prostate carcin oma cell adhesion to bone (Boissier et at, Cancer Res., 57: 3890-3894, 1997 ), Here, we provided evidence that BP pretreatment of breast and prostate c arcinoma cells inhibited tumor cell invasion in a dose-dependent manner. Th e order of potency for four BPs in inhibiting tumor cell invasion was: zole dronate > ibandronate > NE-10244 (active pyridinium analogue of risedronate ) > clodronate, In addition, NE-58051 (the inactive pyridylpropylidene anal ogue of risedronate) had no inhibitory effect, whereas NE-10790 (a phosphon ocarboxylate analogue of risedronate in which one of the phosphonate groups is substituted by a carboxyl group) inhibited tumor cell invasion to an ex tent similar to that observed with NE-10244, indicating that the inhibitory activity of BPs on tumor cells involved the R-2 chain of the molecule, BPs did not induce apoptosis in tumor cells, nor did they inhibit tumor cell m igration at concentrations that did inhibit tumor cell invasion. However, a lthough BPs did not interfere with the production of matrix metalloproteina ses (MMPs) by tumor cells, they inhibited their proteolytic activity. The i nhibitory effect of BPs on MMP activity was completely reversed in the pres ence of an excess of zinc, In addition, NE-10790 did not inhibit MMP activi ty, suggesting that phosphonate groups of BPs are responsible for the chela tion of zinc and the subsequent inhibition of MMP activity. In conclusion, our results provide evidence for a direct cellular effect of BPs in prevent ing tumor cell invasion and an inhibitory effect of BPs on the proteolytic activity of MMPs through zinc chelation, These results suggest, therefore, that BPs may be useful agents for the prophylactic treatment of patients wi th cancers that are known to preferentially metastasize to bone.