Breast cancer frequently spreads to bone and is almost always associated with
osteolysis. This
tumor-induced
osteolysis is caused by increased osteoclastic
bone resorption.
Bisphosphonates are used successfully to inhibit
bone resorption in
tumor bone disease and may prevent development of new osteolytic lesions. The classical view is that
bisphosphonates only act on bone cells. We investigated their effects on
breast cancer cells using three human cell lines, namely, MCF-7, T47D, and MDA.MB.231, and we tested four structurally different
bisphosphonates:
clodronate,
pamidronate,
ibandronate, and
zoledronate. We performed time course studies for each
bisphosphonate at various concentrations and found that all four compounds induced a nonreversible growth inhibition in both MCF-7 and T47D cell lines in a time- and dose-dependent manner. The MDA.MB.231 cell line was less responsive.
Bisphosphonates induced apoptosis in MCF-7 and cell
necrosis in T47D cells. The inhibition of MCF-7 cell proliferation could be reverted almost completely by the
benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl
ketone (
z-VAD-fmk) inhibitor of
caspases, suggesting that the apoptotic process observed in the MCF-7 cell line is mediated, at least partly, by the
caspase system.
Caspase activity was little changed by
bisphosphonates in T47D cells and the inhibitor of
caspase did not modify
bisphosphonates effects. In summary, we found that
bisphosphonates inhibit
breast cancer cell growth by inducing cell death in vitro. Such effects could contribute to the beneficial role of
bisphosphonates in the treatment and the prevention of
tumor-induced
osteolysis.