Bisphosphonates are used as a standard treatment for patients with breast cancer. In vitro studies have shown that bisphosphonates act directly on tumour cells, inhibiting cell proliferation and inducing apoptosis. In most studies, drugs were added to the culture media, thus exposing the cells to bisphosphonates in solution. However, since bisphosphonates bind to bone hydroxyapatite with high affinity and remain bound for very long periods of time, these experimental systems are not an optimal model for the action of the drugs in vivo.
The aim of this study was to determine whether bone-bound zoledronate had direct effects on adjacent breast cancer cells. Bone slices were pre-incubated with bisphosphonate solutions, washed, and seeded with cells of the breast cancer cell lines, MCF7 and MDA-MB-231 cells on bisphosphonate-treated bone indicated increased apoptosis in the cells. Proliferation was assessed by cell counts and thymidine incorporation for up to 72 hours. Inhibition of the mevalonate pathway was tested by measuring the levels of unprenylated Rap1A on western blots.
The proliferation rate of MCF7 and MDA-MB-231 cells seeded on zoledronate-bound bone was significantly lower compared to cells on control bone. Other bisphosphonates tested in this experimental system showed a similar inhibitory effect, with an order of potency that was related to their clinical potencies. Zoledronate induce apoptosis on adjacent MDA-MB-231 cells. Unprenylated Rap1A accumulated in MCF7 and MDA-MB-231 cells seeded on zoledronate-bound bone, suggesting that similar to its mechanism of action in bone cells, zoledronate acted through the inhibition of the mevalonate pathway.
In conclusion, bone-bound zoledronate effectively inhibits breast cancer cell proliferation, an activity that may contribute to its anti-tumour effects seen in the clinic.